rs12527920

Variant names:

• chr6-51831038-C-G
• rs12527920
• NM_138694.4:c.8174-49G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-51831038-C-G
• chr6-51831038-C-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
PKHD1	NM_138694.4	c.8174-49G>C		intron_variant	Intron 51 of 66	ENST00000371117.8	NP_619639.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKHD1	ENST00000371117.8	c.8174-49G>C		intron_variant	Intron 51 of 66	1	NM_138694.4	ENSP00000360158.3
PKHD1	ENST00000340994.4	c.8174-49G>C		intron_variant	Intron 51 of 60	5		ENSP00000341097.4

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

GnomAD2 exomes AF: 0.0532 AC: 11776 AN: 221222 AF XY: 0.0536

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 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

African (AFR) AF: 0.0667 AC: 1979 AN: 29662

American (AMR) AF: 0.0401 AC: 1693 AN: 42208

Ashkenazi Jewish (ASJ) AF: 0.0379 AC: 941 AN: 24806

East Asian (EAS) AF: 0.0849 AC: 3217 AN: 37906

South Asian (SAS) AF: 0.0733 AC: 5933 AN: 80954

European-Finnish (FIN) AF: 0.0568 AC: 2955 AN: 52042

Middle Eastern (MID) AF: 0.0340 AC: 164 AN: 4828

European-Non Finnish (NFE) AF: 0.0484 AC: 46555 AN: 962460

Other (OTH) AF: 0.0493 AC: 2677 AN: 54294

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

African (AFR) AF: 0.0656 AC: 2726 AN: 41534

American (AMR) AF: 0.0370 AC: 566 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3470

East Asian (EAS) AF: 0.0530 AC: 274 AN: 5174

South Asian (SAS) AF: 0.0725 AC: 349 AN: 4816

European-Finnish (FIN) AF: 0.0571 AC: 605 AN: 10596

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0524 AC: 3566 AN: 68020

Other (OTH) AF: 0.0483 AC: 102 AN: 2110

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive polycystic kidney disease Benign:1

Apr 13, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Jul 09, 2018

GeneDx

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	-0.84
CADD	Benign	2.2
DANN	Benign	0.66
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12527920; hg19: chr6-51695836;