rs6130998

Variant names:

• chr20-46024480-C-T
• rs6130998
• NM_001134771.2:c.121+2594C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001134771.2(SLC12A5):​c.121+2594C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 152,166 control chromosomes in the GnomAD database, including 2,714 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 0.18 (2714 hom., cov: 33)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.191
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	NM_001134771.2		c.121+2594C>T		intron	N/A	NP_001128243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000454036.6	TSL:5	c.121+2594C>T		intron	N/A	ENSP00000387694.1
	SLC12A5	ENST00000428198.1	TSL:3	n.111+2594C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26845 AN: 152048 Hom.: 2711 Cov.: 33

Gnomad AFR AF: 0.0868

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.175

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

GnomAD4 genome AF: 0.176 AC: 26852 AN: 152166 Hom.: 2714 Cov.: 33 AF XY: 0.180 AC XY: 13419 AN XY: 74408

African (AFR) AF: 0.0870 AC: 3611 AN: 41516

American (AMR) AF: 0.156 AC: 2386 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 796 AN: 3466

East Asian (EAS) AF: 0.386 AC: 1999 AN: 5178

South Asian (SAS) AF: 0.178 AC: 858 AN: 4818

European-Finnish (FIN) AF: 0.235 AC: 2492 AN: 10586

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14055 AN: 68004

Other (OTH) AF: 0.173 AC: 364 AN: 2108

Alfa AF: 0.186 Hom.: 378

Bravo AF: 0.169

Asia WGS AF: 0.235 AC: 816 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.1
DANN	Benign	0.75
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6130998; hg19: chr20-44653119; COSMIC: COSV54797275; COSMIC: COSV54797275;