Genetic Variant SLC12A5:p.Arg25Arg (chr20-46021840-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001134771.2(SLC12A5):c.75G>A(p.Arg25Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,533,174 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 2 hom. )

Consequence

SLC12A5
NM_001134771.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.776

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 20-46021840-G-A is Benign according to our data. Variant chr20-46021840-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3239235.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.776 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000991 (151/152322) while in subpopulation NFE AF = 0.000191 (13/68026). AF 95% confidence interval is 0.000112. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.75G>A	p.Arg25Arg	synonymous	Exon 1 of 26	NP_001128243.1	Q9H2X9-1
	SLC12A5-AS1	NR_147699.1		n.234C>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.75G>A	p.Arg25Arg	synonymous	Exon 1 of 26	ENSP00000387694.1	Q9H2X9-1
SLC12A5	ENST00000626701.1	TSL:3	c.75G>A	p.Arg25Arg	synonymous	Exon 1 of 3	ENSP00000487372.1	A0A0D9SGD0
SLC12A5	ENST00000628272.1	TSL:3	c.75G>A	p.Arg25Arg	synonymous	Exon 1 of 2	ENSP00000486382.1	A0A0D9SF89

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152210

Hom.:

Cov.:

show subpopulations

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:

0.0130

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000614

AC:

AN:

130394

AF XY:

0.000740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000283

AC:

391

AN:

1380852

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

202

AN XY:

681546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30958

American (AMR)

AF:

0.00

AC:

AN:

35610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25010

East Asian (EAS)

AF:

0.00

AC:

AN:

35404

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79016

European-Finnish (FIN)

AF:

0.0103

AC:

359

AN:

34934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4570

European-Non Finnish (NFE)

AF:

0.0000121

AC:

AN:

1077688

Other (OTH)

AF:

0.000295

AC:

AN:

57662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

107

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

AF:

0.000991

AC:

151

AN:

152322

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0130

AC:

138

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000359

Hom.:

Bravo

AF:

0.0000529

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

0.78

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=100/0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over