rs6032635

Variant names:

• chr20-46049709-G-A
• rs6032635
• NM_020708.5:c.2100G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-46049709-G-A
• chr20-46049709-G-C
• chr20-46049709-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020708.5(SLC12A5):​c.2100G>A​(p.Ala700Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,606,090 control chromosomes in the GnomAD database, including 798,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74062 hom., cov: 32)
  • Exomes 𝑓: 1.0 (724910 hom.)
• Consequence: SLC12A5 NM_020708.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.28
• Publications: 13 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 20-46049709-G-A is Benign according to our data. Variant chr20-46049709-G-A is described in ClinVar as Benign. ClinVar VariationId is 1164899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.2100G>A	p.Ala700Ala	synonymous_variant	Exon 17 of 26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.2169G>A	p.Ala723Ala	synonymous_variant	Exon 17 of 26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2100G>A	p.Ala700Ala	synonymous_variant	Exon 17 of 26	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150060 AN: 152226 Hom.: 74010 Cov.: 32

Gnomad AFR AF: 0.950

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.997 AC: 235819 AN: 236642 AF XY: 0.998

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1451730 AN: 1453746 Hom.: 724910 Cov.: 71 AF XY: 0.999 AC XY: 721217 AN XY: 722064

African (AFR) AF: 0.949 AC: 31736 AN: 33442

American (AMR) AF: 0.997 AC: 43224 AN: 43334

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25794 AN: 25794

East Asian (EAS) AF: 1.00 AC: 39466 AN: 39466

South Asian (SAS) AF: 1.00 AC: 84034 AN: 84044

European-Finnish (FIN) AF: 1.00 AC: 52964 AN: 52964

Middle Eastern (MID) AF: 0.999 AC: 5749 AN: 5756

European-Non Finnish (NFE) AF: 1.00 AC: 1108746 AN: 1108782

Other (OTH) AF: 0.998 AC: 60017 AN: 60164

GnomAD4 genome AF: 0.986 AC: 150170 AN: 152344 Hom.: 74062 Cov.: 32 AF XY: 0.986 AC XY: 73442 AN XY: 74490

African (AFR) AF: 0.950 AC: 39481 AN: 41558

American (AMR) AF: 0.996 AC: 15240 AN: 15306

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5184 AN: 5184

South Asian (SAS) AF: 1.00 AC: 4834 AN: 4834

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68034 AN: 68042

Other (OTH) AF: 0.990 AC: 2094 AN: 2116

Alfa AF: 0.988 Hom.: 45228

Bravo AF: 0.984

Asia WGS AF: 0.996 AC: 3464 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 34 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.4
DANN	Benign	0.65
PhyloP100		-1.3
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6032635; hg19: chr20-44678348; COSMIC: COSV108071025; COSMIC: COSV108071025;