NM_020708.5:c.2855G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020708.5(SLC12A5):c.2855G>A(p.Arg952His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,188 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R952C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 40 hom. )

Consequence

SLC12A5
NM_020708.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 2.97

Publications

31 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: PanelApp Australia, 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, PanelApp Australia, 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007701069).

BP6

Variant 20-46056217-G-A is Benign according to our data. Variant chr20-46056217-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218377.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00135 (205/152332) while in subpopulation SAS AF = 0.0145 (70/4828). AF 95% confidence interval is 0.0118. There are 2 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020708.5. 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_020708.5	MANE Select	c.2855G>A	p.Arg952His	missense	Exon 22 of 26	NP_065759.1	Q9H2X9-2
	SLC12A5	NM_001134771.2		c.2924G>A	p.Arg975His	missense	Exon 22 of 26	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC12A5	ENST00000243964.7	TSL:1 MANE Select	c.2855G>A	p.Arg952His	missense	Exon 22 of 26	ENSP00000243964.4	Q9H2X9-2
SLC12A5	ENST00000616202.4	TSL:1	c.613-2264G>A		intron	N/A	ENSP00000478369.1	M4PM71
SLC12A5	ENST00000626937.2	TSL:1	c.510-3382G>A		intron	N/A	ENSP00000485953.1	M4PNC0

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

206

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00335

AC:

842

AN:

251422

AF XY:

0.00435

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00913

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00216

AC:

3159

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

2029

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.000492

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00995

AC:

260

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0190

AC:

1636

AN:

86256

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000955

AC:

1062

AN:

1111994

Other (OTH)

AF:

0.00219

AC:

132

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

198

396

595

793

991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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

AF:

0.00135

AC:

205

AN:

152332

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000216

AC:

AN:

41580

American (AMR)

AF:

0.000523

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5188

South Asian (SAS)

AF:

0.0145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

68022

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.000990

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00335

AC:

407

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Developmental and epileptic encephalopathy, 34 (3)

Epilepsy, idiopathic generalized, susceptibility to, 14 (3)

not provided (1)

SLC12A5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0077

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

PhyloP100

3.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.3

REVEL

Pathogenic

0.67

Sift

Benign

0.057

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.73

MVP

0.36

MPC

0.21

ClinPred

0.010

GERP RS

3.9

Varity_R

0.071

gMVP

0.70

Mutation Taster

=71/29

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over