15-34230478-C-T

Position:

• chr15-34230478-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001365088.1(SLC12A6):​c.*3403G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 152,376 control chromosomes in the GnomAD database, including 27,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (27663 hom., cov: 32)
  • Exomes 𝑓: 0.75 (100 hom.)
• Consequence: SLC12A6 NM_001365088.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0190

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 15-34230478-C-T is Benign according to our data. Variant chr15-34230478-C-T is described in ClinVar as [Benign]. Clinvar id is 315550.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A6	NM_001365088.1	c.*3403G>A		3_prime_UTR_variant	26/26	ENST00000354181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC12A6	ENST00000354181.8	c.*3403G>A		3_prime_UTR_variant	26/26	1	NM_001365088.1	A1
SLC12A6	ENST00000290209.9	c.*3403G>A		3_prime_UTR_variant	25/25	1		P3
SLC12A6	ENST00000676379.1	c.*2022G>A		3_prime_UTR_variant	26/26

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88850 AN: 151904 Hom.: 27660 Cov.: 32

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.600

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.618

GnomAD4 exome AF: 0.751 AC: 266 AN: 354 Hom.: 100 Cov.: 0 AF XY: 0.741 AC XY: 163 AN XY: 220

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.756

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.800

GnomAD4 genome AF: 0.585 AC: 88885 AN: 152022 Hom.: 27663 Cov.: 32 AF XY: 0.590 AC XY: 43835 AN XY: 74302

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.636

Gnomad4 EAS AF: 0.692

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.677

Gnomad4 OTH AF: 0.619

Alfa AF: 0.654 Hom.: 32025

Bravo AF: 0.572

Asia WGS AF: 0.641 AC: 2228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Agenesis of the corpus callosum with peripheral neuropathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.8
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs4530104; hg19: chr15-34522679;