rs2277869

Variant names:

• chr12-907744-T-C
• rs2277869
• ENST00000540885.1:n.25T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-907744-T-C
• chr12-907744-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000540885.1(WNK1):​n.25T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,360,380 control chromosomes in the GnomAD database, including 17,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (1886 hom., cov: 32)
  • Exomes 𝑓: 0.16 (15891 hom.)
• Consequence: WNK1 ENST00000540885.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.237
• Publications: 18 publications found

Genes affected

WNK1 (HGNC:14540): (WNK lysine deficient protein kinase 1) This gene encodes a member of the WNK subfamily of serine/threonine protein kinases. The encoded protein may be a key regulator of blood pressure by controlling the transport of sodium and chloride ions. Mutations in this gene have been associated with pseudohypoaldosteronism type II and hereditary sensory neuropathy type II. Alternatively spliced transcript variants encoding different isoforms have been described but the full-length nature of all of them has yet to be determined.[provided by RefSeq, May 2010]

WNK1 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• pseudohypoaldosteronism type 2C

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary sensory and autonomic neuropathy type 2

  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 (BayesDel_noAF=-0.6).
• BP6: Variant 12-907744-T-C is Benign according to our data. Variant chr12-907744-T-C is described in ClinVar as Benign. ClinVar VariationId is 1229228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK1	NM_213655.5	c.7400-103T>C		intron_variant	Intron 26 of 27	ENST00000340908.9	NP_998820.3
WNK1	NM_018979.4	c.6644-103T>C		intron_variant	Intron 26 of 27	ENST00000315939.11	NP_061852.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK1	ENST00000340908.9	c.7400-103T>C		intron_variant	Intron 26 of 27	5	NM_213655.5	ENSP00000341292.5
WNK1	ENST00000315939.11	c.6644-103T>C		intron_variant	Intron 26 of 27	1	NM_018979.4	ENSP00000313059.6

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23972 AN: 152130 Hom.: 1881 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0939

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.163

GnomAD4 exome AF: 0.160 AC: 193302 AN: 1208132 Hom.: 15891 Cov.: 17 AF XY: 0.161 AC XY: 98630 AN XY: 613550

African (AFR) AF: 0.172 AC: 4859 AN: 28326

American (AMR) AF: 0.213 AC: 9440 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3579 AN: 24606

East Asian (EAS) AF: 0.114 AC: 4382 AN: 38536

South Asian (SAS) AF: 0.195 AC: 15701 AN: 80494

European-Finnish (FIN) AF: 0.113 AC: 5805 AN: 51562

Middle Eastern (MID) AF: 0.181 AC: 667 AN: 3676

European-Non Finnish (NFE) AF: 0.159 AC: 140662 AN: 884718

Other (OTH) AF: 0.158 AC: 8207 AN: 51854

GnomAD4 genome AF: 0.158 AC: 24002 AN: 152248 Hom.: 1886 Cov.: 32 AF XY: 0.156 AC XY: 11597 AN XY: 74440

African (AFR) AF: 0.165 AC: 6863 AN: 41546

American (AMR) AF: 0.198 AC: 3031 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3472

East Asian (EAS) AF: 0.0935 AC: 484 AN: 5176

South Asian (SAS) AF: 0.183 AC: 886 AN: 4832

European-Finnish (FIN) AF: 0.111 AC: 1175 AN: 10606

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10536 AN: 68006

Other (OTH) AF: 0.161 AC: 341 AN: 2114

Alfa AF: 0.160 Hom.: 2806

Bravo AF: 0.163

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		-0.24
Mutation Taster		=99/1	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: rs2277869; hg19: chr12-1016910; COSMIC: COSV57272285; COSMIC: COSV57272285;