NM_000338.3:c.2873T>G

Variant names:

• chr15-48288516-T-G
• NM_000338.3:c.2873T>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000338.3(SLC12A1):​c.2873T>G​(p.Val958Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V958A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC12A1 NM_000338.3 missense, splice_region
• Scores: Splicing: ADA: 0.00002974
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.777

Genes affected

SLC12A1 (HGNC:10910): (solute carrier family 12 member 1) This gene encodes a kidney-specific sodium-potassium-chloride cotransporter that is expressed on the luminal membrane of renal epithelial cells of the thick ascending limb of Henle's loop and the macula densa. It plays a key role in concentrating urine and accounts for most of the NaCl resorption. It is sensitive to such diuretics as furosemide and bumetanide. Some Bartter-like syndromes result from defects in this gene. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their biological validity in humans has not been experimentally proven.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0648261).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A1	NM_000338.3	c.2873T>G	p.Val958Gly	missense_variant, splice_region_variant	Exon 23 of 27	ENST00000380993.8	NP_000329.2
SLC12A1	NM_001184832.2	c.2873T>G	p.Val958Gly	missense_variant, splice_region_variant	Exon 23 of 27		NP_001171761.1
SLC12A1	NM_001384136.1	c.2873T>G	p.Val958Gly	missense_variant, splice_region_variant	Exon 23 of 27		NP_001371065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A1	ENST00000380993.8	c.2873T>G	p.Val958Gly	missense_variant, splice_region_variant	Exon 23 of 27	5	NM_000338.3	ENSP00000370381.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with SLC12A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 958 of the SLC12A1 protein (p.Val958Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.14	.;.;T;T;T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.32	.;T;.;.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.065	T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	-1.3	N;.;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.11	.;.;.;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.17	.;.;.;T;T;T
Sift4G	Benign	0.35	.;.;.;T;T;T
Polyphen		0.0	.;.;B;B;B;.
Vest4		0.062, 0.061
MutPred		0.44		Loss of stability (P = 0.0047);.;Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);
MVP		0.77
MPC		0.18
ClinPred		0.32	T
GERP RS		4.5
Varity_R		0.061
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.056
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-48580713;