ENST00000561080.5:n.*155G>C

Variant names:

• chr15-34237407-C-G
• rs11854257
• ENST00000561080.5:n.*155G>C

Variant summary

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

The ENST00000561080.5(SLC12A6):​n.*155G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,609,038 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (101 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (88 hom.)
• Consequence: SLC12A6 ENST00000561080.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.343
• Publications: 1 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=-0.82).
• BP6: Variant 15-34237407-C-G is Benign according to our data. Variant chr15-34237407-C-G is described in ClinVar as Benign. ClinVar VariationId is 159895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000561080.5. 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.2934+12G>C		intron	N/A	NP_001352017.1
	SLC12A6	NM_133647.2		c.2934+12G>C		intron	N/A	NP_598408.1
	SLC12A6	NM_001042496.2		c.2907+12G>C		intron	N/A	NP_001035961.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000561080.5	TSL:1	n.*155G>C		non_coding_transcript_exon	Exon 21 of 25	ENSP00000454069.1
	SLC12A6	ENST00000561080.5	TSL:1	n.*155G>C		3_prime_UTR	Exon 21 of 25	ENSP00000454069.1
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.2934+12G>C		intron	N/A	ENSP00000346112.3

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2905 AN: 151868 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.0666

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00749

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00515 AC: 1295 AN: 251376 AF XY: 0.00400

Gnomad AFR exome AF: 0.0708

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00188 AC: 2739 AN: 1457052 Hom.: 88 Cov.: 30 AF XY: 0.00161 AC XY: 1169 AN XY: 724944

African (AFR) AF: 0.0649 AC: 2162 AN: 33320

American (AMR) AF: 0.00343 AC: 153 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52950

Middle Eastern (MID) AF: 0.00453 AC: 26 AN: 5744

European-Non Finnish (NFE) AF: 0.000124 AC: 137 AN: 1108814

Other (OTH) AF: 0.00413 AC: 248 AN: 60086

GnomAD4 genome AF: 0.0191 AC: 2908 AN: 151986 Hom.: 101 Cov.: 32 AF XY: 0.0187 AC XY: 1389 AN XY: 74280

African (AFR) AF: 0.0665 AC: 2755 AN: 41428

American (AMR) AF: 0.00748 AC: 114 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67994

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00276 Hom.: 5

Bravo AF: 0.0214

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	15
DANN	Benign	0.32
PhyloP100		0.34
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: rs11854257; hg19: chr15-34529608;