rs12527920

chr6-51831038-C-Gchr6-51831038-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):c.8174-49G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0516 in 1,441,370 control chromosomes in the GnomAD database, including 2,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (240 hom., cov: 32)
  • Exomes 𝑓: 0.051 (1960 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.774

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 (BayesDel_noAF=-0.84).
• BP6: Variant 6-51831038-C-G is Benign according to our data. Variant chr6-51831038-C-G is described in ClinVar as [Benign]. Clinvar id is 262420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKHD1	NM_138694.4	c.8174-49G>C		intron_variant		ENST00000371117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKHD1	ENST00000371117.8	c.8174-49G>C		intron_variant		1	NM_138694.4	P2
PKHD1	ENST00000340994.4	c.8174-49G>C		intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8296 AN: 152092 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0369

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.0524

Gnomad SAS AF: 0.0726

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0455

GnomAD3 exomes AF: 0.0532 AC: 11776 AN: 221222 Hom.: 344 AF XY: 0.0536 AC XY: 6438 AN XY: 120046

Gnomad AFR exome AF: 0.0666

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.0356

Gnomad EAS exome AF: 0.0344

Gnomad SAS exome AF: 0.0772

Gnomad FIN exome AF: 0.0585

Gnomad NFE exome AF: 0.0519

Gnomad OTH exome AF: 0.0606

GnomAD4 exome AF: 0.0513 AC: 66114 AN: 1289160 Hom.: 1960 Cov.: 18 AF XY: 0.0522 AC XY: 33854 AN XY: 649146

Gnomad4 AFR exome AF: 0.0667

Gnomad4 AMR exome AF: 0.0401

Gnomad4 ASJ exome AF: 0.0379

Gnomad4 EAS exome AF: 0.0849

Gnomad4 SAS exome AF: 0.0733

Gnomad4 FIN exome AF: 0.0568

Gnomad4 NFE exome AF: 0.0484

Gnomad4 OTH exome AF: 0.0493

GnomAD4 genome AF: 0.0547 AC: 8327 AN: 152210 Hom.: 240 Cov.: 32 AF XY: 0.0548 AC XY: 4079 AN XY: 74428

Gnomad4 AFR AF: 0.0656

Gnomad4 AMR AF: 0.0370

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.0530

Gnomad4 SAS AF: 0.0725

Gnomad4 FIN AF: 0.0571

Gnomad4 NFE AF: 0.0524

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0571 Hom.: 48

Bravo AF: 0.0522

Asia WGS AF: 0.0980 AC: 340 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 13, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.2
Dann	Benign	0.66

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: rs12527920; hg19: chr6-51695836; COSMIC: COSV61872448;