rs41273726

Variant names:

• chr6-52028309-T-C
• rs41273726
• NM_138694.4:c.3407A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-52028309-T-C
• chr6-52028309-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.3407A>G​(p.Tyr1136Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00846 in 1,614,058 control chromosomes in the GnomAD database, including 114 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1136N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0084 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (103 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: -0.0580
• Publications: 21 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010802239).
• BP6: Variant 6-52028309-T-C is Benign according to our data. Variant chr6-52028309-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167489.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00842 (1282/152242) while in subpopulation NFE AF = 0.014 (955/68004). AF 95% confidence interval is 0.0133. There are 11 homozygotes in GnomAd4. There are 587 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.3407A>G	p.Tyr1136Cys	missense	Exon 30 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.3407A>G	p.Tyr1136Cys	missense	Exon 30 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.3407A>G	p.Tyr1136Cys	missense	Exon 30 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.3407A>G	p.Tyr1136Cys	missense	Exon 30 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.00843 AC: 1282 AN: 152124 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00764 AC: 1921 AN: 251458 AF XY: 0.00737

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00846 AC: 12371 AN: 1461816 Hom.: 103 Cov.: 31 AF XY: 0.00865 AC XY: 6289 AN XY: 727218

African (AFR) AF: 0.00105 AC: 35 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 422 AN: 26136

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

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86256

European-Finnish (FIN) AF: 0.0127 AC: 678 AN: 53420

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5720

European-Non Finnish (NFE) AF: 0.00949 AC: 10550 AN: 1111992

Other (OTH) AF: 0.00669 AC: 404 AN: 60388

GnomAD4 genome AF: 0.00842 AC: 1282 AN: 152242 Hom.: 11 Cov.: 32 AF XY: 0.00789 AC XY: 587 AN XY: 74436

African (AFR) AF: 0.00132 AC: 55 AN: 41542

American (AMR) AF: 0.00248 AC: 38 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 955 AN: 68004

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0117 Hom.: 56

Bravo AF: 0.00606

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00790 AC: 959

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.00771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	Autosomal recessive polycystic kidney disease (6)
-	-	5	not provided (5)
-	-	2	not specified (2)
-	1	-	Caroli disease (1)
-	-	1	Polycystic kidney disease (1)
-	-	1	Polycystic kidney disease 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.5
DANN	Benign	0.94
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.058
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.38
MVP		0.91
MPC		0.075
ClinPred		0.050	T
GERP RS		0.46
Varity_R		0.12
gMVP		0.51
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs41273726; hg19: chr6-51893107; COSMIC: COSV61870616;