5-128083995-G-T

Position:

• chr5-128083995-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001046.3(SLC12A2):​c.41G>T​(p.Gly14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,249,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SLC12A2 NM_001046.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.47

Genes affected

SLC12A2 (HGNC:10911): (solute carrier family 12 member 2) The protein encoded by this gene mediates sodium and chloride transport and reabsorption. The encoded protein is a membrane protein and is important in maintaining proper ionic balance and cell volume. This protein is phosphorylated in response to DNA damage. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13081327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A2	NM_001046.3	c.41G>T	p.Gly14Val	missense_variant	1/27	ENST00000262461.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A2	ENST00000262461.7	c.41G>T	p.Gly14Val	missense_variant	1/27	1	NM_001046.3	P4
SLC12A2	ENST00000343225.4	c.41G>T	p.Gly14Val	missense_variant	1/26	1		A2
SLC12A2	ENST00000509205.5	c.41G>T	p.Gly14Val	missense_variant, NMD_transcript_variant	1/27	1
SLC12A2	ENST00000628403.2	c.41G>T	p.Gly14Val	missense_variant	1/26	5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151704 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000960

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097540 Hom.: 0 Cov.: 30 AF XY: 0.00000955 AC XY: 5 AN XY: 523820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000485

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000738

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000107

Gnomad4 OTH exome AF: 0.0000457

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151704 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74098

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000960

Bravo AF: 0.000280

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.41G>T (p.G14V) alteration is located in exon 1 (coding exon 1) of the SLC12A2 gene. This alteration results from a G to T substitution at nucleotide position 41, causing the glycine (G) at amino acid position 14 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Kilquist syndrome;C5436768:Hearing loss, autosomal dominant 78;C5436771:Delpire-McNeill syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 14 of the SLC12A2 protein (p.Gly14Val). This variant is present in population databases (no rsID available, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SLC12A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1365125). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC12A2 protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.0030	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	0.99	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.19	N;.;N
REVEL	Benign	0.22
Sift	Benign	0.15	T;.;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.12
MutPred		0.15		Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);
MVP		0.22
MPC		0.87
ClinPred		0.26	T
GERP RS		3.9
Varity_R		0.074
gMVP		0.26

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: rs1014756958; hg19: chr5-127419687;