Genetic Variant SLC12A5:c.612+571G>T (chr20-46037956-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020708.5(SLC12A5):c.612+571G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 152,040 control chromosomes in the GnomAD database, including 6,857 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 6857 hom., cov: 31)

Consequence

SLC12A5
NM_020708.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

Publications

12 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5 link	c.612+571G>T		intron_variant	Intron 6 of 25	ENST00000243964.7	NP_065759.1	Q9H2X9-2
SLC12A5	NM_001134771.2 link	c.681+571G>T		intron_variant	Intron 6 of 25		NP_001128243.1	Q9H2X9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7 link	c.612+571G>T		intron_variant	Intron 6 of 25	1	NM_020708.5	ENSP00000243964.4		Q9H2X9-2

Frequencies

GnomAD3 genomes

AF:

0.272

AC:

41366

AN:

151922

Hom.:

6863

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0818

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.273

Gnomad ASJ

AF:

0.361

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.348

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.376

Gnomad OTH

AF:

0.298

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.272

AC:

41353

AN:

152040

Hom.:

6857

Cov.:

AF XY:

0.271

AC XY:

20155

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0815

AC:

3385

AN:

41524

American (AMR)

AF:

0.273

AC:

4168

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

1251

AN:

3470

East Asian (EAS)

AF:

0.206

AC:

1065

AN:

5162

South Asian (SAS)

AF:

0.239

AC:

1148

AN:

4810

European-Finnish (FIN)

AF:

0.348

AC:

3677

AN:

10556

Middle Eastern (MID)

AF:

0.344

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.376

AC:

25555

AN:

67934

Other (OTH)

AF:

0.295

AC:

622

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1410

2821

4231

5642

7052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.335

Hom.:

30544

Bravo

AF:

0.257

Asia WGS

AF:

0.194

AC:

678

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

8.1

(source)

DANN

Benign

0.75

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism (auto)

(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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20-46037956-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over