Genetic Variant NM_001134771.2:c.8G>A (chr20-46021773-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001134771.2(SLC12A5):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,380,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC12A5
NM_001134771.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18408999).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134771.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_001134771.2		c.8G>A	p.Arg3His	missense	Exon 1 of 26	NP_001128243.1	Q9H2X9-1
	SLC12A5-AS1	NR_147699.1		n.301C>T		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A5	ENST00000454036.6	TSL:5	c.8G>A	p.Arg3His	missense	Exon 1 of 26	ENSP00000387694.1	Q9H2X9-1
SLC12A5	ENST00000626701.1	TSL:3	c.8G>A	p.Arg3His	missense	Exon 1 of 3	ENSP00000487372.1	A0A0D9SGD0
SLC12A5	ENST00000628272.1	TSL:3	c.8G>A	p.Arg3His	missense	Exon 1 of 2	ENSP00000486382.1	A0A0D9SF89

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1380962

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681738

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31012

American (AMR)

AF:

0.00

AC:

AN:

35772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25020

East Asian (EAS)

AF:

0.00

AC:

AN:

35420

South Asian (SAS)

AF:

0.00

AC:

AN:

79070

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4340

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1078252

Other (OTH)

AF:

0.00

AC:

AN:

57688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.020

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.0

PhyloP100

1.3

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.11

REVEL

Benign

0.26

Sift

Benign

0.15

Sift4G

Benign

0.16

Polyphen

0.23

Vest4

0.20

MutPred

0.20

Loss of MoRF binding (P = 0.0146)

MVP

0.62

MPC

1.2

ClinPred

0.50

GERP RS

4.6

PromoterAI

0.00030

Neutral

(source)

Varity_R

0.13

gMVP

0.25

Mutation Taster

=77/23

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over