10-100288427-C-T

Position:

• chr10-100288427-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_016112.3(PKD2L1):​c.2387G>A​(p.Arg796His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,612,830 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (23 hom.)
• Consequence: PKD2L1 NM_016112.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.74

Genes affected

PKD2L1 (HGNC:9011): (polycystin 2 like 1, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein contains multiple transmembrane domains, and cytoplasmic N- and C-termini. The protein may be an integral membrane protein involved in cell-cell/matrix interactions. This protein functions as a calcium-regulated nonselective cation channel. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033938587).
• BP6: Variant 10-100288427-C-T is Benign according to our data. Variant chr10-100288427-C-T is described in ClinVar as [Benign]. Clinvar id is 720318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 161 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2L1	NM_016112.3	c.2387G>A	p.Arg796His	missense_variant	16/16	ENST00000318222.4	NP_057196.2
PKD2L1	NM_001253837.2	c.2246G>A	p.Arg749His	missense_variant	16/16		NP_001240766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2L1	ENST00000318222.4	c.2387G>A	p.Arg796His	missense_variant	16/16	1	NM_016112.3	ENSP00000325296.3
PKD2L1	ENST00000528248.1	n.*2127G>A		non_coding_transcript_exon_variant	16/16	1		ENSP00000436514.1
PKD2L1	ENST00000528248.1	n.*2127G>A		3_prime_UTR_variant	16/16	1		ENSP00000436514.1
PKD2L1	ENST00000465680.2	c.155G>A	p.Arg52His	missense_variant	2/2	3		ENSP00000434019.1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00232 AC: 582 AN: 251344 Hom.: 11 AF XY: 0.00308 AC XY: 418 AN XY: 135848

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0123

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00142 AC: 2077 AN: 1460534 Hom.: 23 Cov.: 28 AF XY: 0.00186 AC XY: 1349 AN XY: 726694

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000617

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74462

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000929

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00237 AC: 288

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.17
DANN	Benign	0.60
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.075
Sift	Benign	0.55	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.014
MVP		0.26
MPC		0.082
ClinPred		0.011	T
GERP RS		-6.6
Varity_R		0.024
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs142439136; hg19: chr10-102048184; COSMIC: COSV58394378; COSMIC: COSV58394378;