6-51883145-T-A

Variant names:

• chr6-51883145-T-A
• rs76895755
• NM_138694.4:c.7298A>T

Variant summary

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

The NM_138694.4(PKHD1):​c.7298A>T​(p.Asp2433Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,612,624 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.28

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007316977).
• BP6: Variant 6-51883145-T-A is Benign according to our data. Variant chr6-51883145-T-A is described in ClinVar as [Benign]. Clinvar id is 167483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1530/152288) while in subpopulation AFR AF= 0.034 (1413/41540). AF 95% confidence interval is 0.0325. There are 29 homozygotes in gnomad4. There are 703 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.7298A>T	p.Asp2433Val	missense_variant	Exon 46 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.7298A>T	p.Asp2433Val	missense_variant	Exon 46 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.7298A>T	p.Asp2433Val	missense_variant	Exon 46 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1524 AN: 152170 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00275 AC: 690 AN: 251176 Hom.: 12 AF XY: 0.00197 AC XY: 267 AN XY: 135758

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00108 AC: 1577 AN: 1460336 Hom.: 28 Cov.: 30 AF XY: 0.000950 AC XY: 690 AN XY: 726594

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000729

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.0100 AC: 1530 AN: 152288 Hom.: 29 Cov.: 32 AF XY: 0.00944 AC XY: 703 AN XY: 74472

Gnomad4 AFR AF: 0.0340

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00168 Hom.: 5

Bravo AF: 0.0120

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 18, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKHD1 c.7298A>T (p.Asp2433Val) results in a non-conservative amino acid change located in the Pectin lyase fold (IPR012334) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 282570 control chromosomes, predominantly at a frequency of 0.035 within the African or African-American subpopulation in the gnomAD database, including 20 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.7298A>T in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submission (evaluation after 2014) classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:2

May 11, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 27, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0073	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D;N
REVEL	Uncertain	0.40
Sift	Benign	0.039	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.67	P;P
Vest4		0.58
MVP		0.97
MPC		0.27
ClinPred		0.023	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs76895755; hg19: chr6-51747943;