Genetic Variant NM_001134771.2:c.74G>C (chr20-46021839-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS1

The NM_001134771.2(SLC12A5):c.74G>C(p.Arg25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,381,186 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.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC12A5
NM_001134771.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.853

Variant links:

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 links:

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

SLC12A5-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07580912).

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00000579 (8/1381186) while in subpopulation SAS AF= 0.0000506 (4/79034). AF 95% confidence interval is 0.0000168. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_001134771.2 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 26		NP_001128243.1	Q9H2X9-1
SLC12A5-AS1	NR_147699.1 link	n.235C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
SLC12A5	ENST00000454036.6 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 26	5	ENSP00000387694.1	Q9H2X9-1
SLC12A5	ENST00000626701.1 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 3	3	ENSP00000487372.1	A0A0D9SGD0
SLC12A5	ENST00000628272.1 link	c.74G>C	p.Arg25Pro	missense_variant	Exon 1 of 2	3	ENSP00000486382.1	A0A0D9SF89

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152204

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000478

GnomAD4 exome

AF:

0.00000579

AC:

AN:

1381186

Hom.:

Cov.:

AF XY:

0.00000733

AC XY:

AN XY:

681748

show subpopulations

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:

0.0000506

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000371

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.000478

Alfa

AF:

0.0000728

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.065

T;.;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.66

T;T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.076

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.34

N;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.39

N;.;.

REVEL

Benign

0.12

Sift

Benign

0.26

T;.;.

Sift4G

Benign

0.27

T;D;D

Polyphen

0.0

B;.;.

Vest4

0.12

MutPred

0.18

Loss of stability (P = 0.0592);Loss of stability (P = 0.0592);Loss of stability (P = 0.0592);

MVP

0.27

MPC

1.3

ClinPred

0.13

GERP RS

2.9

Varity_R

0.13

gMVP

0.40

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over