rs2499481

Variant names:

• chr6-52026124-C-G
• rs2499481
• NM_138694.4:c.3686G>C

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.3686G>C​(p.Trp1229Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,614,094 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.896
• Publications: 3 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=0.008166671).
• BP6: Variant 6-52026124-C-G is Benign according to our data. Variant chr6-52026124-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0099 (1507/152252) while in subpopulation AFR AF = 0.0334 (1388/41538). AF 95% confidence interval is 0.032. There are 33 homozygotes in GnomAd4. There are 662 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.3686G>C	p.Trp1229Ser	missense	Exon 32 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.3686G>C	p.Trp1229Ser	missense	Exon 32 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.3686G>C	p.Trp1229Ser	missense	Exon 32 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.3686G>C	p.Trp1229Ser	missense	Exon 32 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.00991 AC: 1508 AN: 152134 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00276 AC: 688 AN: 249532 AF XY: 0.00197

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000331

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00112 AC: 1633 AN: 1461842 Hom.: 26 Cov.: 36 AF XY: 0.00100 AC XY: 728 AN XY: 727224

African (AFR) AF: 0.0319 AC: 1069 AN: 33480

American (AMR) AF: 0.00333 AC: 149 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53392

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.000210 AC: 234 AN: 1111990

Other (OTH) AF: 0.00230 AC: 139 AN: 60396

GnomAD4 genome AF: 0.00990 AC: 1507 AN: 152252 Hom.: 33 Cov.: 32 AF XY: 0.00889 AC XY: 662 AN XY: 74448

African (AFR) AF: 0.0334 AC: 1388 AN: 41538

American (AMR) AF: 0.00556 AC: 85 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68010

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00308 Hom.: 2

Bravo AF: 0.0114

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00350 AC: 425

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive polycystic kidney disease (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Polycystic kidney disease 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.68
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.65	N
PhyloP100		0.90
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.098
Sift	Benign	0.96	T
Sift4G	Benign	0.73	T
Polyphen		0.010	B
Vest4		0.29
MVP		0.84
MPC		0.096
ClinPred		0.0035	T
GERP RS		3.1
Varity_R		0.14
gMVP		0.41
Mutation Taster		=97/3	polymorphism

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: rs2499481; hg19: chr6-51890922;