16-2115436-T-A

Position:

• chr16-2115436-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001009944.3(PKD1):​c.2039A>T​(p.Tyr680Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,592,892 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: PKD1 NM_001009944.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.00900

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072483122).
• BP6: Variant 16-2115436-T-A is Benign according to our data. Variant chr16-2115436-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 256930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2115436-T-A is described in Lovd as [Benign]. Variant chr16-2115436-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0005 (76/152032) while in subpopulation EAS AF= 0.0134 (69/5148). AF 95% confidence interval is 0.0109. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD1	NM_001009944.3	c.2039A>T	p.Tyr680Phe	missense_variant	10/46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9	c.2039A>T	p.Tyr680Phe	missense_variant	10/46	1	NM_001009944.3	ENSP00000262304	P5
PKD1	ENST00000423118.5	c.2039A>T	p.Tyr680Phe	missense_variant	10/46	1		ENSP00000399501	A2
PKD1	ENST00000488185.2	c.472+2053A>T		intron_variant		5		ENSP00000456672
PKD1	ENST00000568591.5	c.*367A>T		3_prime_UTR_variant, NMD_transcript_variant	6/12	2		ENSP00000457162

Frequencies

GnomAD3 genomes AF: 0.000494 AC: 75 AN: 151914 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0132

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000975 AC: 206 AN: 211218 Hom.: 0 AF XY: 0.000940 AC XY: 108 AN XY: 114928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.0126

Gnomad SAS exome AF: 0.000147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.000376

GnomAD4 exome AF: 0.000329 AC: 474 AN: 1440860 Hom.: 2 Cov.: 32 AF XY: 0.000331 AC XY: 237 AN XY: 715570

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.0102

Gnomad4 SAS exome AF: 0.000203

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000363

Gnomad4 OTH exome AF: 0.000925

GnomAD4 genome AF: 0.000500 AC: 76 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0134

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000855 Hom.: 0

Bravo AF: 0.000620

ExAC AF: 0.000796 AC: 95

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 01, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD1 p.Tyr680Phe variant was identified in 2 of 98 proband chromosomes (frequency: 0.020) from individuals or families with ADPKD in the Chinese population. Family analysis showed that the variant does not co-segregate with ADPKD and was classified as a probable polymorphism (Liu 2015, Xiao-Ping 2012). The variant was also identified in dbSNP (ID: rs370141157) as “with likely benign allele”; in the Clinvitae and Clinvar databases (as likely benign by Prevention Genetics) and in ADPKD Mutation Database 2x as likely neutral. The variant was further identified in the 1000 Genomes Project in 16 of 5000 chromosomes (frequency: 0.0032); the genome Aggregation Database (February 27, 2017) in 217 of 237604 chromosomes (freq. 0.001); and in the Exome Aggregation Consortium database (August 8th 2016) in 73 of 33700 chromosomes (freq. 0.002) in the following populations: East Asian in 69 of 1894 chromosomes (freq. 0.036), South Asian in 2 of 8840 chromosomes (freq. 0.0002), European (Non-Finnish) in 1of 17664 chromosomes (freq. 0.0001), other in 1 of 280 chromosomes and not seen in the African and Finnish populations increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The variant was not identified in GeneInsight COGR, MutDB, PKD1-LOVD and PKD1-LOVD 3.0 databases and the NHLBI GO Exome Sequencing Project. In addition the variant was identified with a co-occurring pathogenic PKD2 variant (p.Arg803X), increasing the likelihood that the p.Tyr680Phe variant does not have clinical significance. The p.Tyr680 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.11
Sift	Benign	0.16	T;T
Sift4G	Benign	0.23	T;T
Polyphen		1.0	D;P
Vest4		0.43
MutPred		0.60		Loss of glycosylation at P679 (P = 0.1187);Loss of glycosylation at P679 (P = 0.1187);
MVP		0.77
ClinPred		0.039	T
GERP RS		2.8
Varity_R		0.051
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs370141157; hg19: chr16-2165437;