rs2290941

Variant names:

• chr15-34252150-C-A
• rs2290941
• NM_001365088.1:c.1333+20G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133647.2(SLC12A6):​c.1333+20G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,314,282 control chromosomes in the GnomAD database, including 21,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2170 hom., cov: 31)
  • Exomes 𝑓: 0.18 (18893 hom.)
• Consequence: SLC12A6 NM_133647.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.495
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-34252150-C-A is Benign according to our data. Variant chr15-34252150-C-A is described in ClinVar as Benign. ClinVar VariationId is 139120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133647.2. 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
	SLC12A6	NM_001365088.1	MANE Select	c.1333+20G>T		intron	N/A	NP_001352017.1
	SLC12A6	NM_133647.2		c.1333+20G>T		intron	N/A	NP_598408.1
	SLC12A6	NM_001042496.2		c.1306+20G>T		intron	N/A	NP_001035961.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.1333+20G>T		intron	N/A	ENSP00000346112.3
	SLC12A6	ENST00000560611.5	TSL:1	c.1333+20G>T		intron	N/A	ENSP00000454168.1
	SLC12A6	ENST00000558589.5	TSL:1	c.1306+20G>T		intron	N/A	ENSP00000452776.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25222 AN: 151836 Hom.: 2174 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.181

GnomAD2 exomes AF: 0.187 AC: 45594 AN: 243860 AF XY: 0.189

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.183

Gnomad EAS exome AF: 0.278

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.178 AC: 206889 AN: 1162328 Hom.: 18893 Cov.: 16 AF XY: 0.180 AC XY: 106540 AN XY: 592542

African (AFR) AF: 0.125 AC: 3452 AN: 27596

American (AMR) AF: 0.188 AC: 8210 AN: 43712

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4569 AN: 24202

East Asian (EAS) AF: 0.249 AC: 9509 AN: 38220

South Asian (SAS) AF: 0.224 AC: 17863 AN: 79790

European-Finnish (FIN) AF: 0.172 AC: 9115 AN: 52930

Middle Eastern (MID) AF: 0.282 AC: 1460 AN: 5182

European-Non Finnish (NFE) AF: 0.171 AC: 143438 AN: 840164

Other (OTH) AF: 0.184 AC: 9273 AN: 50532

GnomAD4 genome AF: 0.166 AC: 25223 AN: 151954 Hom.: 2170 Cov.: 31 AF XY: 0.168 AC XY: 12505 AN XY: 74258

African (AFR) AF: 0.127 AC: 5275 AN: 41434

American (AMR) AF: 0.178 AC: 2709 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 661 AN: 3472

East Asian (EAS) AF: 0.284 AC: 1465 AN: 5160

South Asian (SAS) AF: 0.226 AC: 1086 AN: 4814

European-Finnish (FIN) AF: 0.159 AC: 1673 AN: 10550

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11740 AN: 67956

Other (OTH) AF: 0.180 AC: 380 AN: 2108

Alfa AF: 0.167 Hom.: 464

Bravo AF: 0.165

Asia WGS AF: 0.227 AC: 791 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Agenesis of the corpus callosum with peripheral neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		0.49
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: rs2290941; hg19: chr15-34544351; COSMIC: COSV51626598; COSMIC: COSV51626598;