rs2435322

Variant names:

• chr6-52010452-A-C
• rs2435322
• NM_138694.4:c.5608T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-52010452-A-C
• chr6-52010452-A-G
• chr6-52010452-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.5608T>G​(p.Leu1870Val) variant causes a missense change. The variant allele was found at a frequency of 0.993 in 1,597,222 control chromosomes in the GnomAD database, including 787,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1870G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.96 (70599 hom., cov: 30)
  • Exomes 𝑓: 1.0 (717097 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.28
• Publications: 37 publications found

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_138694.4
• BP4: Computational evidence support a benign effect (MetaRNN=5.6595013E-7).
• BP6: Variant 6-52010452-A-C is Benign according to our data. Variant chr6-52010452-A-C is described in ClinVar as Benign. ClinVar VariationId is 96410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.5608T>G	p.Leu1870Val	missense	Exon 35 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.5608T>G	p.Leu1870Val	missense	Exon 35 of 61	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.5608T>G	p.Leu1870Val	missense	Exon 35 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.5608T>G	p.Leu1870Val	missense	Exon 35 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146193 AN: 152086 Hom.: 70555 Cov.: 30

Gnomad AFR AF: 0.865

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.974

GnomAD2 exomes AF: 0.990 AC: 248675 AN: 251296 AF XY: 0.993

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.996 AC: 1439260 AN: 1445018 Hom.: 717097 Cov.: 31 AF XY: 0.997 AC XY: 717668 AN XY: 720126

African (AFR) AF: 0.860 AC: 28461 AN: 33088

American (AMR) AF: 0.993 AC: 44356 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26010 AN: 26034

East Asian (EAS) AF: 1.00 AC: 39614 AN: 39614

South Asian (SAS) AF: 1.00 AC: 85871 AN: 85902

European-Finnish (FIN) AF: 1.00 AC: 53412 AN: 53412

Middle Eastern (MID) AF: 0.994 AC: 5609 AN: 5642

European-Non Finnish (NFE) AF: 1.00 AC: 1096600 AN: 1096800

Other (OTH) AF: 0.991 AC: 59327 AN: 59840

GnomAD4 genome AF: 0.961 AC: 146293 AN: 152204 Hom.: 70599 Cov.: 30 AF XY: 0.963 AC XY: 71696 AN XY: 74416

African (AFR) AF: 0.865 AC: 35874 AN: 41480

American (AMR) AF: 0.986 AC: 15088 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3469 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5175 AN: 5176

South Asian (SAS) AF: 1.00 AC: 4804 AN: 4806

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68006 AN: 68038

Other (OTH) AF: 0.974 AC: 2057 AN: 2112

Alfa AF: 0.985 Hom.: 156288

Bravo AF: 0.955

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 0.999 AC: 3852

ESP6500AA AF: 0.866 AC: 3814

ESP6500EA AF: 0.999 AC: 8592

ExAC AF: 0.987 AC: 119853

Asia WGS AF: 0.993 AC: 3453 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Autosomal recessive polycystic kidney disease (4)
-	-	2	not specified (2)
-	-	2	Polycystic kidney disease 4 (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.029
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.16
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.0	N
PhyloP100		5.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	1.8	N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.060
ClinPred		0.010	T
GERP RS		5.6
Varity_R		0.092
gMVP		0.63
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2435322; hg19: chr6-51875250; COSMIC: COSV107435372;