rs371762181

Positions:

• chr16-2097484-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001009944.3(PKD1):​c.10240G>A​(p.Gly3414Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,602,250 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.91

Genes affected

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 16-2097484-C-T is Benign according to our data. Variant chr16-2097484-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 433999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2097484-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.10240G>A	p.Gly3414Ser	missense_variant	33/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.10240G>A	p.Gly3414Ser	missense_variant	33/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.10237G>A	p.Gly3413Ser	missense_variant	33/46	1		ENSP00000399501	A2
PKD1	ENST00000487932.5	c.*1433G>A		3_prime_UTR_variant, NMD_transcript_variant	20/30	5		ENSP00000457132

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000394 AC: 94 AN: 238586 Hom.: 0 AF XY: 0.000458 AC XY: 60 AN XY: 131078

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0000681

Gnomad NFE exome AF: 0.000729

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000714 AC: 1035 AN: 1449912 Hom.: 1 Cov.: 33 AF XY: 0.000702 AC XY: 507 AN XY: 721848

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000464

Gnomad4 NFE exome AF: 0.000865

Gnomad4 OTH exome AF: 0.000581

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74496

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.000450

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000467 AC: 4

ExAC AF: 0.000364 AC: 44

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 08, 2024

Variant summary: PKD1 c.10240G>A (p.Gly3414Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 238586 control chromosomes, predominantly at a frequency of 0.00073 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKD1 causing Polycystic Kidney Disease 1 phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.10240G>A in individuals affected with Polycystic Kidney Disease 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 433999). Based on the evidence outlined above, the variant was classified as likely benign. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Polycystic kidney disease Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1, p.Gly3414Ser variant was identified in 1 of 478 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD, and was not identified in 58 control chromosomes from healthy individuals. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and the variant was defined as novel and likely polymorphic (Rossetti 2007); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in dbSNP (ID: rs371762181) as “NA”, in the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and in NHLBI GO Exome Sequencing Project in 4 of 8558 European American (frequency: 0.0005). Furthermore, the variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 43 of 113264 chromosomes (frequency: 0.0004) from a population of 38 in 61472 (0.0006) European Non-Finnish; 4 in 16412 (0.0002) in South Asian; and 1 in 11328 (0.00009) Latino populations. The variant was also listed in the ADPKD Mutation Database (2x as likely neutral) but was not identified in Clinvitae, ClinVar, GeneInsight COGR MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases. The p.Gly3414 residue is not conserved in mammals and the variant amino acid Serine is present in, Macaque, Rat, Mouse, Dog, Opossum and in Zebra finch increasing the likelihood that this variant does not have clinical significance. Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of the consensus splice site; however, HumanSpliceFinder and MaxEntScan predict an altered 3' splice site in this region and we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.62
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.3	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.0	N;N
REVEL	Benign	0.11
Sift	Benign	0.94	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.024	B;B
Vest4		0.15
MVP		0.38
ClinPred		0.0091	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs371762181; hg19: chr16-2147485;