6-51906249-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_138694.4(PKHD1):​c.6774A>C​(p.Val2258Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000949 in 1,611,776 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00049 ( 0 hom., cov: 32)
Exomes š‘“: 0.000053 ( 1 hom. )

Consequence

PKHD1
NM_138694.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -1.13
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 6-51906249-T-G is Benign according to our data. Variant chr6-51906249-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262410.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BP7
Synonymous conserved (PhyloP=-1.13 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PKHD1NM_138694.4 linkc.6774A>C p.Val2258Val synonymous_variant Exon 41 of 67 ENST00000371117.8 NP_619639.3 P08F94-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKHD1ENST00000371117.8 linkc.6774A>C p.Val2258Val synonymous_variant Exon 41 of 67 1 NM_138694.4 ENSP00000360158.3 P08F94-1
PKHD1ENST00000340994.4 linkc.6774A>C p.Val2258Val synonymous_variant Exon 41 of 61 5 ENSP00000341097.4 P08F94-2

Frequencies

GnomAD3 genomes
AF:
0.000460
AC:
70
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00164
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000128
AC:
32
AN:
250832
Hom.:
1
AF XY:
0.000103
AC XY:
14
AN XY:
135542
show subpopulations
Gnomad AFR exome
AF:
0.00191
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000534
AC:
78
AN:
1459504
Hom.:
1
Cov.:
28
AF XY:
0.0000482
AC XY:
35
AN XY:
726246
show subpopulations
Gnomad4 AFR exome
AF:
0.00213
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.000493
AC:
75
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.000618
AC XY:
46
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00176
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000332
Hom.:
0
Bravo
AF:
0.000567

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive polycystic kidney disease Uncertain:1Benign:2
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jun 01, 2018
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Jul 14, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance: Likely 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
-0.80
CADD
Benign
0.17
DANN
Benign
0.59

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34796823; hg19: chr6-51771047; API