Genetic Variant NM_020708.5:c.2330G>T (chr20-46051823-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020708.5(SLC12A5):c.2330G>T(p.Arg777Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,423,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R777H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SLC12A5
NM_020708.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.14

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 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 34
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
epilepsy of infancy with migrating focal seizures
Inheritance: AR Classification: STRONG Submitted by: G2P
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, idiopathic generalized, susceptibility to, 14
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics
genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

SLC12A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31182975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5 link	c.2330G>T	p.Arg777Leu	missense_variant	Exon 18 of 26	ENST00000243964.7	NP_065759.1	Q9H2X9-2
SLC12A5	NM_001134771.2 link	c.2399G>T	p.Arg800Leu	missense_variant	Exon 18 of 26		NP_001128243.1	Q9H2X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 link	c.2330G>T	p.Arg777Leu	missense_variant	Exon 18 of 26	1	NM_020708.5	ENSP00000243964.4		Q9H2X9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1423372

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31510

American (AMR)

AF:

0.00

AC:

AN:

40184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24956

East Asian (EAS)

AF:

0.00

AC:

AN:

35776

South Asian (SAS)

AF:

0.00

AC:

AN:

82850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1094616

Other (OTH)

AF:

0.00

AC:

AN:

58596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.040

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.81

L;.

PhyloP100

3.1

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.32

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.034

B;B

Vest4

0.56

MutPred

0.44

Loss of MoRF binding (P = 0.0045);.;

MVP

0.91

MPC

1.3

ClinPred

0.77

GERP RS

4.0

Varity_R

0.31

gMVP

0.86

Mutation Taster

=44/56

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over