rs76572975

Variant names:

• chr6-51632705-C-A
• rs76572975
• NM_138694.4:c.11525G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-51632705-C-A
• chr6-51632705-C-T
• chr6-51632705-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138694.4(PKHD1):​c.11525G>T​(p.Arg3842Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,612,948 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3842Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.021 (406 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.69
• Publications: 19 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), 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 (MetaRNN=0.0076598525).
• BP6: Variant 6-51632705-C-A is Benign according to our data. Variant chr6-51632705-C-A is described in ClinVar as Benign. ClinVar VariationId is 96371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2633/151962) while in subpopulation NFE AF = 0.0231 (1572/67968). AF 95% confidence interval is 0.0222. There are 35 homozygotes in GnomAd4. There are 1347 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.11525G>T	p.Arg3842Leu	missense	Exon 65 of 67	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.11525G>T	p.Arg3842Leu	missense	Exon 65 of 67	ENSP00000360158.3	P08F94-1

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2636 AN: 151844 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00423

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0189 AC: 4729 AN: 250844 AF XY: 0.0192

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0416

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0207 AC: 30239 AN: 1460986 Hom.: 406 Cov.: 31 AF XY: 0.0207 AC XY: 15058 AN XY: 726798

African (AFR) AF: 0.00472 AC: 158 AN: 33442

American (AMR) AF: 0.0123 AC: 551 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 601 AN: 26108

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.00899 AC: 775 AN: 86232

European-Finnish (FIN) AF: 0.0378 AC: 2020 AN: 53390

Middle Eastern (MID) AF: 0.0485 AC: 279 AN: 5758

European-Non Finnish (NFE) AF: 0.0223 AC: 24815 AN: 1111374

Other (OTH) AF: 0.0172 AC: 1037 AN: 60340

GnomAD4 genome AF: 0.0173 AC: 2633 AN: 151962 Hom.: 35 Cov.: 32 AF XY: 0.0181 AC XY: 1347 AN XY: 74240

African (AFR) AF: 0.00427 AC: 177 AN: 41472

American (AMR) AF: 0.0177 AC: 269 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4820

European-Finnish (FIN) AF: 0.0437 AC: 460 AN: 10516

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1572 AN: 67968

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.0199 Hom.: 82

Bravo AF: 0.0153

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0223 AC: 86

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0243 AC: 209

ExAC AF: 0.0177 AC: 2150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	3	not specified (3)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.50
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	-0.0021	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.32
Sift	Benign	0.12	T
Sift4G	Benign	1.0	T
Polyphen		0.99	D
Vest4		0.13
MPC		0.12
ClinPred		0.037	T
GERP RS		5.7
Varity_R		0.18
gMVP		0.50
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76572975; hg19: chr6-51497503; COSMIC: COSV64386744;