rs62406036

Variant names:

• chr6-52056905-A-G
• rs62406036
• NM_138694.4:c.1587T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138694.4(PKHD1):​c.1587T>C​(p.Asn529Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0681 in 1,612,956 control chromosomes in the GnomAD database, including 4,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (298 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3902 hom.)
• Consequence: PKHD1 NM_138694.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.02
• Publications: 13 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 6-52056905-A-G is Benign according to our data. Variant chr6-52056905-A-G is described in ClinVar as Benign. ClinVar VariationId is 96378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 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.1587T>C	p.Asn529Asn	synonymous	Exon 17 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.1587T>C	p.Asn529Asn	synonymous	Exon 17 of 61	NP_733842.2	P08F94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.1587T>C	p.Asn529Asn	synonymous	Exon 17 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.1587T>C	p.Asn529Asn	synonymous	Exon 17 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8040 AN: 152054 Hom.: 298 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0396

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.0997

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0667

Gnomad OTH AF: 0.0432

GnomAD2 exomes AF: 0.0665 AC: 16707 AN: 251138 AF XY: 0.0699

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.0910

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0563

GnomAD4 exome AF: 0.0697 AC: 101863 AN: 1460784 Hom.: 3902 Cov.: 31 AF XY: 0.0706 AC XY: 51277 AN XY: 726778

African (AFR) AF: 0.00998 AC: 334 AN: 33476

American (AMR) AF: 0.0333 AC: 1488 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 1304 AN: 26126

East Asian (EAS) AF: 0.117 AC: 4636 AN: 39680

South Asian (SAS) AF: 0.0970 AC: 8363 AN: 86226

European-Finnish (FIN) AF: 0.0911 AC: 4863 AN: 53408

Middle Eastern (MID) AF: 0.0267 AC: 154 AN: 5766

European-Non Finnish (NFE) AF: 0.0691 AC: 76798 AN: 1111026

Other (OTH) AF: 0.0650 AC: 3923 AN: 60352

GnomAD4 genome AF: 0.0528 AC: 8039 AN: 152172 Hom.: 298 Cov.: 32 AF XY: 0.0552 AC XY: 4105 AN XY: 74404

African (AFR) AF: 0.0119 AC: 496 AN: 41524

American (AMR) AF: 0.0395 AC: 604 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3472

East Asian (EAS) AF: 0.109 AC: 562 AN: 5176

South Asian (SAS) AF: 0.100 AC: 482 AN: 4814

European-Finnish (FIN) AF: 0.0997 AC: 1056 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0667 AC: 4537 AN: 67998

Other (OTH) AF: 0.0432 AC: 91 AN: 2106

Alfa AF: 0.0600 Hom.: 193

Bravo AF: 0.0459

Asia WGS AF: 0.106 AC: 368 AN: 3474

EpiCase AF: 0.0613

EpiControl AF: 0.0638

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)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.2
DANN	Benign	0.87
PhyloP100		3.0
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: rs62406036; hg19: chr6-51921703; COSMIC: COSV61877195;