chr20-46021881-T-G

Variant names:

• chr20-46021881-T-G
• rs759067394
• NM_001134771.2:c.116T>G

Variant summary

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

The NM_001134771.2(SLC12A5):​c.116T>G​(p.Val39Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,374,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V39F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SLC12A5 NM_001134771.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101

Genes affected

SLC12A5 (HGNC:13818): (solute carrier family 12 member 5) K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]

SLC12A5-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

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=0.06881958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_001134771.2	c.116T>G	p.Val39Gly	missense_variant	Exon 1 of 26		NP_001128243.1
SLC12A5-AS1	NR_147699.1	n.193A>C		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000454036.6	c.116T>G	p.Val39Gly	missense_variant	Exon 1 of 26	5		ENSP00000387694.1
SLC12A5	ENST00000626701.1	c.116T>G	p.Val39Gly	missense_variant	Exon 1 of 3	3		ENSP00000487372.1
SLC12A5	ENST00000413737.2	c.41T>G	p.Val14Gly	missense_variant	Exon 1 of 3	3		ENSP00000487291.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1374012 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 677892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000288

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.049	T;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.049	T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.80	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.33	T;.;.
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.10
MutPred		0.20		Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);
MVP		0.27
MPC		1.2
ClinPred		0.093	T
GERP RS		0.51
Varity_R		0.056
gMVP		0.44

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759067394; hg19: chr20-44650520;