rs113562492

Variant names:

• chr6-51775841-T-C
• rs113562492
• NM_138694.4:c.8521A>G
• PKHD1 p.Met2841Val

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_138694.4(PKHD1):​c.8521A>G​(p.Met2841Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,582,968 control chromosomes in the GnomAD database, including 32 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2841I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (22 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.519
• Publications: 9 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: Orphanet, ClinGen, Myriad Women's Health
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in NM_138694.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0040930808).
• BP6: Variant 6-51775841-T-C is Benign according to our data. Variant chr6-51775841-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188742.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00657 (999/152054) while in subpopulation AFR AF = 0.0201 (835/41554). AF 95% confidence interval is 0.019. There are 10 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.8521A>G	p.Met2841Val	missense	Exon 54 of 67	NP_619639.3
	PKHD1	NM_170724.3		c.8521A>G	p.Met2841Val	missense	Exon 54 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.8521A>G	p.Met2841Val	missense	Exon 54 of 67	ENSP00000360158.3	P08F94-1
	PKHD1	ENST00000340994.4	TSL:5	c.8521A>G	p.Met2841Val	missense	Exon 54 of 61	ENSP00000341097.4	P08F94-2

Frequencies

GnomAD3 genomes AF: 0.00654 AC: 993 AN: 151936 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00263

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.00283 AC: 708 AN: 249804 AF XY: 0.00245

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000390

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00135 AC: 1933 AN: 1430914 Hom.: 22 Cov.: 26 AF XY: 0.00126 AC XY: 898 AN XY: 713738

African (AFR) AF: 0.0227 AC: 743 AN: 32782

American (AMR) AF: 0.00130 AC: 58 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.0235 AC: 608 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.0000817 AC: 7 AN: 85680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52730

Middle Eastern (MID) AF: 0.00386 AC: 22 AN: 5706

European-Non Finnish (NFE) AF: 0.000230 AC: 249 AN: 1084872

Other (OTH) AF: 0.00415 AC: 246 AN: 59248

GnomAD4 genome AF: 0.00657 AC: 999 AN: 152054 Hom.: 10 Cov.: 32 AF XY: 0.00655 AC XY: 487 AN XY: 74330

African (AFR) AF: 0.0201 AC: 835 AN: 41554

American (AMR) AF: 0.00263 AC: 40 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3464

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000354 AC: 24 AN: 67860

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00350 Hom.: 13

Bravo AF: 0.00793

Asia WGS AF: 0.00491 AC: 17 AN: 3476

EpiCase AF: 0.000710

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Autosomal recessive polycystic kidney disease (4)
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.9
DANN	Benign	0.44
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.52
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.23
Sift	Benign	0.085	T
Sift4G	Uncertain	0.057	T
Varity_R		0.13
gMVP		0.54
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113562492;

hg19: chr6-51640639;

COSMIC: COSV99049454;