rs9474034

Variant names:

• chr6-51632721-C-T
• rs9474034
• NM_138694.4:c.11509G>A

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.11509G>A​(p.Val3837Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00856 in 1,612,518 control chromosomes in the GnomAD database, including 1,046 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V3837V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (561 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (485 hom.)
• Consequence: PKHD1 NM_138694.4 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.671
• Publications: 12 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=0.0017229617).
• BP6: Variant 6-51632721-C-T is Benign according to our data. Variant chr6-51632721-C-T is described in ClinVar as Benign. ClinVar VariationId is 96370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

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.11509G>A	p.Val3837Ile	missense splice_region	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.11509G>A	p.Val3837Ile	missense splice_region	Exon 65 of 67	ENSP00000360158.3	P08F94-1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6920 AN: 151908 Hom.: 560 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0118 AC: 2952 AN: 250810 AF XY: 0.00859

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.00754

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000512

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00471 AC: 6872 AN: 1460492 Hom.: 485 Cov.: 31 AF XY: 0.00412 AC XY: 2990 AN XY: 726606

African (AFR) AF: 0.163 AC: 5426 AN: 33390

American (AMR) AF: 0.00949 AC: 424 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000557 AC: 48 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00834 AC: 48 AN: 5756

European-Non Finnish (NFE) AF: 0.000286 AC: 318 AN: 1110990

Other (OTH) AF: 0.0100 AC: 606 AN: 60318

GnomAD4 genome AF: 0.0456 AC: 6936 AN: 152026 Hom.: 561 Cov.: 32 AF XY: 0.0451 AC XY: 3354 AN XY: 74288

African (AFR) AF: 0.158 AC: 6564 AN: 41434

American (AMR) AF: 0.0169 AC: 257 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67996

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0168 Hom.: 511

Bravo AF: 0.0523

ESP6500AA AF: 0.153 AC: 672

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0149 AC: 1813

Asia WGS AF: 0.00953 AC: 34 AN: 3476

EpiCase AF: 0.000492

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.67
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.18
Sift	Benign	0.062	T
Sift4G	Benign	0.26	T
Polyphen		0.16	B
Vest4		0.018
MPC		0.062
ClinPred		0.0066	T
GERP RS		4.8
Varity_R		0.043
gMVP		0.18
Mutation Taster		=83/17	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: rs9474034; hg19: chr6-51497519; COSMIC: COSV64383939;