rs2499482

Variant names:

• chr6-52025934-G-A
• rs2499482
• NM_138694.4:c.3876C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138694.4(PKHD1):​c.3876C>T​(p.Thr1292Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,614,142 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0620

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-52025934-G-A is Benign according to our data. Variant chr6-52025934-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.062 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00995 (1515/152288) while in subpopulation AFR AF= 0.0335 (1393/41566). AF 95% confidence interval is 0.032. There are 33 homozygotes in gnomad4. There are 666 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.3876C>T	p.Thr1292Thr	synonymous_variant	Exon 32 of 67	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.3876C>T	p.Thr1292Thr	synonymous_variant	Exon 32 of 67	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.3876C>T	p.Thr1292Thr	synonymous_variant	Exon 32 of 61	5		ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1516 AN: 152170 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00276 AC: 691 AN: 250680 Hom.: 12 AF XY: 0.00198 AC XY: 269 AN XY: 135552

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000336

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00112 AC: 1636 AN: 1461854 Hom.: 26 Cov.: 35 AF XY: 0.00100 AC XY: 727 AN XY: 727236

Gnomad4 AFR exome AF: 0.0319

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00995 AC: 1515 AN: 152288 Hom.: 33 Cov.: 32 AF XY: 0.00895 AC XY: 666 AN XY: 74452

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00433 Hom.: 5

Bravo AF: 0.0114

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 09, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PKHD1 c.3876C>T (p.Thr1292Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. This variant was found in 419/120698 control chromosomes (including 9 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.035141 (359/10216). This frequency is about 5 times the estimated maximal expected allele frequency of a pathogenic PKHD1 variant (0.0070711), suggesting this is a benign polymorphism found primarily in the populations of African origin. In addition, one clinical diagnostic laboratory has classified this variant as benign. Taken together, this variant is classified as Benign. -

Jan 22, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.46
DANN	Benign	0.28

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: rs2499482; hg19: chr6-51890732;