rs426634

Variant names:

• chr15-34279723-C-T
• rs426634
• NM_001365088.1:c.272-4334G>A

Variant summary

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

The NM_001365088.1(SLC12A6):​c.272-4334G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 152,112 control chromosomes in the GnomAD database, including 14,300 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 0.38 (14300 hom., cov: 32)
• Consequence: SLC12A6 NM_001365088.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.203
• Publications: 7 publications found

Genes affected

SLC12A6 (HGNC:10914): (solute carrier family 12 member 6) This gene is a member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The proteins encoded by this gene are activated by cell swelling induced by hypotonic conditions. Alternate splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy. [provided by RefSeq, Jul 2008]

SLC12A6 Gene-Disease associations (from GenCC):

• agenesis of the corpus callosum with peripheral neuropathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease, axonal, IIa 2II

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365088.1. 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
	SLC12A6	NM_001365088.1	MANE Select	c.272-4334G>A		intron	N/A	NP_001352017.1
	SLC12A6	NM_133647.2		c.272-4334G>A		intron	N/A	NP_598408.1
	SLC12A6	NM_001042496.2		c.245-4334G>A		intron	N/A	NP_001035961.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.272-4334G>A		intron	N/A	ENSP00000346112.3
	SLC12A6	ENST00000560611.5	TSL:1	c.272-4334G>A		intron	N/A	ENSP00000454168.1
	SLC12A6	ENST00000558589.5	TSL:1	c.245-4334G>A		intron	N/A	ENSP00000452776.1

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58411 AN: 151994 Hom.: 14270 Cov.: 32

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.385 AC: 58499 AN: 152112 Hom.: 14300 Cov.: 32 AF XY: 0.379 AC XY: 28208 AN XY: 74356

African (AFR) AF: 0.706 AC: 29284 AN: 41468

American (AMR) AF: 0.253 AC: 3875 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1003 AN: 3468

East Asian (EAS) AF: 0.322 AC: 1670 AN: 5180

South Asian (SAS) AF: 0.362 AC: 1746 AN: 4826

European-Finnish (FIN) AF: 0.202 AC: 2137 AN: 10576

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17621 AN: 67990

Other (OTH) AF: 0.328 AC: 693 AN: 2112

Alfa AF: 0.300 Hom.: 4138

Bravo AF: 0.401

Asia WGS AF: 0.329 AC: 1146 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.15
PhyloP100		0.20
Mutation Taster		=100/0	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: rs426634; hg19: chr15-34571924;