chr5-128084073-C-T

Position:

• chr5-128084073-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000262461.7(SLC12A2):​c.119C>T​(p.Pro40Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000858 in 1,165,712 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 (★). Synonymous variant affecting the same amino acid position (i.e. P40P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: SLC12A2 ENST00000262461.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.277

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09608722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC12A2	NM_001046.3	c.119C>T	p.Pro40Leu	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.119C>T	p.Pro40Leu	missense_variant	1/27	1	NM_001046.3	ENSP00000262461	P4
SLC12A2	ENST00000343225.4	c.119C>T	p.Pro40Leu	missense_variant	1/26	1		ENSP00000340878	A2
SLC12A2	ENST00000509205.5	c.119C>T	p.Pro40Leu	missense_variant, NMD_transcript_variant	1/27	1		ENSP00000427109
SLC12A2	ENST00000628403.2	c.119C>T	p.Pro40Leu	missense_variant	1/26	5		ENSP00000486323

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.58e-7 AC: 1 AN: 1165712 Hom.: 0 Cov.: 30 AF XY: 0.00000176 AC XY: 1 AN XY: 567586

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Delpire-McNeill syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

May 20, 2023

The observed missense c.119C>T(p.Pro40Leu) variant in SLC12A2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in gnomAD Exomes. The amino acid Pro at position 40 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Pro40Leu in SLC12A2 is predicted as conserved by PhyloP across 100 vertebrates. Computational evidence (Polyphen - Benign, SIFT - Damaging, and MutationTaster - Polymorphism) predicts conflicting evidence on protein structure and function for this variant. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L;.;L
MutationTaster	Benign	0.97	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.19	N;.;N
REVEL	Benign	0.17
Sift	Benign	0.21	T;.;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0	B;.;B
Vest4		0.083
MutPred		0.33		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.14
MPC		0.71
ClinPred		0.20	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.31

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: rs964331045; hg19: chr5-127419765;