rs9381994

Variant names:

• chr6-51619163-T-C
• rs9381994
• NM_138694.4:c.12143A>G

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.12143A>G​(p.Gln4048Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,613,906 control chromosomes in the GnomAD database, including 248,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21709 hom., cov: 35)
  • Exomes 𝑓: 0.56 (227239 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.422
• Publications: 38 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

ENSG00000228689 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0750294E-5).
• BP6: Variant 6-51619163-T-C is Benign according to our data. Variant chr6-51619163-T-C is described in ClinVar as Benign. ClinVar VariationId is 96376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.624 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.12143A>G	p.Gln4048Arg	missense	Exon 67 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.12143A>G	p.Gln4048Arg	missense	Exon 67 of 67	ENSP00000360158.3
	ENSG00000228689	ENST00000454361.1	TSL:3	n.81-3192T>C		intron	N/A
	ENSG00000228689	ENST00000589278.6	TSL:5	n.811-3197T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.533 AC: 81013 AN: 152104 Hom.: 21711 Cov.: 35

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.524

GnomAD2 exomes AF: 0.566 AC: 142135 AN: 250914 AF XY: 0.566

Gnomad AFR exome AF: 0.479

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.585

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.548

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.556 AC: 813130 AN: 1461684 Hom.: 227239 Cov.: 52 AF XY: 0.558 AC XY: 406037 AN XY: 727146

African (AFR) AF: 0.475 AC: 15907 AN: 33474

American (AMR) AF: 0.637 AC: 28473 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 12850 AN: 26136

East Asian (EAS) AF: 0.591 AC: 23451 AN: 39696

South Asian (SAS) AF: 0.626 AC: 53966 AN: 86256

European-Finnish (FIN) AF: 0.531 AC: 28346 AN: 53402

Middle Eastern (MID) AF: 0.573 AC: 3304 AN: 5762

European-Non Finnish (NFE) AF: 0.552 AC: 613819 AN: 1111858

Other (OTH) AF: 0.547 AC: 33014 AN: 60380

GnomAD4 genome AF: 0.532 AC: 81035 AN: 152222 Hom.: 21709 Cov.: 35 AF XY: 0.532 AC XY: 39565 AN XY: 74412

African (AFR) AF: 0.478 AC: 19869 AN: 41532

American (AMR) AF: 0.580 AC: 8875 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1696 AN: 3468

East Asian (EAS) AF: 0.587 AC: 3033 AN: 5170

South Asian (SAS) AF: 0.643 AC: 3100 AN: 4822

European-Finnish (FIN) AF: 0.510 AC: 5397 AN: 10592

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37434 AN: 68010

Other (OTH) AF: 0.522 AC: 1104 AN: 2114

Alfa AF: 0.545 Hom.: 100866

Bravo AF: 0.536

TwinsUK AF: 0.549 AC: 2035

ALSPAC AF: 0.551 AC: 2125

ESP6500AA AF: 0.481 AC: 2120

ESP6500EA AF: 0.549 AC: 4719

ExAC AF: 0.563 AC: 68311

Asia WGS AF: 0.597 AC: 2076 AN: 3476

EpiCase AF: 0.549

EpiControl AF: 0.554

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	3	Polycystic kidney disease 4 (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	0.074
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.42
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.21
Sift	Benign	0.52	T
Sift4G	Benign	0.25	T
Polyphen		0.031	B
Vest4		0.021
MPC		0.064
ClinPred		0.010	T
GERP RS		4.0
Varity_R		0.046
gMVP		0.16
Mutation Taster		=86/14	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: rs9381994; hg19: chr6-51483961; COSMIC: COSV64381840; COSMIC: COSV64381840;