chr5-128084110-C-G

Position:

• chr5-128084110-C-G

Variant summary

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

The NM_001046.3(SLC12A2):​c.156C>G​(p.Asp52Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,310,550 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (12 hom.)
• Consequence: SLC12A2 NM_001046.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.63

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023020804).
• BP6: Variant 5-128084110-C-G is Benign according to our data. Variant chr5-128084110-C-G is described in ClinVar as [Benign]. Clinvar id is 1599916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A2	NM_001046.3	c.156C>G	p.Asp52Glu	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.156C>G	p.Asp52Glu	missense_variant	1/27	1	NM_001046.3	ENSP00000262461	P4
SLC12A2	ENST00000343225.4	c.156C>G	p.Asp52Glu	missense_variant	1/26	1		ENSP00000340878	A2
SLC12A2	ENST00000509205.5	c.156C>G	p.Asp52Glu	missense_variant, NMD_transcript_variant	1/27	1		ENSP00000427109
SLC12A2	ENST00000628403.2	c.156C>G	p.Asp52Glu	missense_variant	1/26	5		ENSP00000486323

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 177 AN: 151596 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000885

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00513 AC: 96 AN: 18730 Hom.: 3 AF XY: 0.00691 AC XY: 78 AN XY: 11292

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000597

Gnomad ASJ exome AF: 0.00315

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0180

Gnomad FIN exome AF: 0.000705

Gnomad NFE exome AF: 0.00157

Gnomad OTH exome AF: 0.00172

GnomAD4 exome AF: 0.00134 AC: 1557 AN: 1158846 Hom.: 12 Cov.: 30 AF XY: 0.00157 AC XY: 883 AN XY: 563498

Gnomad4 AFR exome AF: 0.000212

Gnomad4 AMR exome AF: 0.000496

Gnomad4 ASJ exome AF: 0.00384

Gnomad4 EAS exome AF: 0.000115

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.0000791

Gnomad4 NFE exome AF: 0.000814

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00117 AC: 178 AN: 151704 Hom.: 0 Cov.: 32 AF XY: 0.00143 AC XY: 106 AN XY: 74152

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000885

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000953 Hom.: 0

Bravo AF: 0.000933

ExAC AF: 0.00412 AC: 86

Asia WGS AF: 0.00815 AC: 28 AN: 3328

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SLC12A2: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.9
DANN	Benign	0.66
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.060	N;.;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.049
MutPred		0.070		Gain of methylation at R57 (P = 0.1338);Gain of methylation at R57 (P = 0.1338);Gain of methylation at R57 (P = 0.1338);
MVP		0.34
MPC		0.65
ClinPred		0.0090	T
GERP RS		0.62
Varity_R		0.037
gMVP		0.18

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: rs540907216; hg19: chr5-127419802; COSMIC: COSV105106598; COSMIC: COSV105106598;