chr5-128084138-G-A

Position:

• chr5-128084138-G-A

Variant summary

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

The NM_001046.3(SLC12A2):​c.184G>A​(p.Ala62Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,145,594 control chromosomes in the GnomAD database, including 1 homozygotes. 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: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: SLC12A2 NM_001046.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.368

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=0.20566356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A2	NM_001046.3	c.184G>A	p.Ala62Thr	missense_variant	1/27	ENST00000262461.7	NP_001037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC12A2	ENST00000262461.7	c.184G>A	p.Ala62Thr	missense_variant	1/27	1	NM_001046.3	ENSP00000262461	P4
SLC12A2	ENST00000343225.4	c.184G>A	p.Ala62Thr	missense_variant	1/26	1		ENSP00000340878	A2
SLC12A2	ENST00000509205.5	c.184G>A	p.Ala62Thr	missense_variant, NMD_transcript_variant	1/27	1		ENSP00000427109
SLC12A2	ENST00000628403.2	c.184G>A	p.Ala62Thr	missense_variant	1/26	5		ENSP00000486323

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000227 AC: 26 AN: 1145594 Hom.: 1 Cov.: 31 AF XY: 0.0000180 AC XY: 10 AN XY: 556046

Gnomad4 AFR exome AF: 0.000348

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000406

Gnomad4 NFE exome AF: 0.00000208

Gnomad4 OTH exome AF: 0.000328

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000312 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

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. 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. This variant has not been reported in the literature in individuals affected with SLC12A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 62 of the SLC12A2 protein (p.Ala62Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.0	L;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.080	N;.;N
REVEL	Benign	0.16
Sift	Benign	0.40	T;.;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.23
MutPred		0.23		Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);Gain of relative solvent accessibility (P = 0.0023);
MVP		0.35
MPC		0.67
ClinPred		0.047	T
GERP RS		-0.12
Varity_R		0.028
gMVP		0.28

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: rs542192991; hg19: chr5-127419830;