15-34230209-T-C

Variant names:

• chr15-34230209-T-C
• rs182573709
• NM_001365088.1:c.*3672A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001365088.1(SLC12A6):​c.*3672A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00667 in 173,460 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (0 hom.)
• Consequence: SLC12A6 NM_001365088.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.362

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]

EMC4 (HGNC:28032): (ER membrane protein complex subunit 4) Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane. Part of EMC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 15-34230209-T-C is Benign according to our data. Variant chr15-34230209-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 884493.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00649 (988/152274) while in subpopulation NFE AF= 0.00966 (657/68016). AF 95% confidence interval is 0.00905. There are 5 homozygotes in gnomad4. There are 456 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A6	NM_001365088.1	c.*3672A>G		3_prime_UTR_variant	Exon 26 of 26	ENST00000354181.8	NP_001352017.1
EMC4	NM_016454.4	c.*421T>C		downstream_gene_variant		ENST00000267750.9	NP_057538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A6	ENST00000354181	c.*3672A>G		3_prime_UTR_variant	Exon 26 of 26	1	NM_001365088.1	ENSP00000346112.3
EMC4	ENST00000267750.9	c.*421T>C		downstream_gene_variant		1	NM_016454.4	ENSP00000267750.4

Frequencies

GnomAD3 genomes AF: 0.00651 AC: 990 AN: 152156 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00753

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00967

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.00798 AC: 169 AN: 21186 Hom.: 0 Cov.: 0 AF XY: 0.00775 AC XY: 86 AN XY: 11090

Gnomad4 AFR exome AF: 0.00154

Gnomad4 AMR exome AF: 0.00816

Gnomad4 ASJ exome AF: 0.00820

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00495

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00649 AC: 988 AN: 152274 Hom.: 5 Cov.: 33 AF XY: 0.00612 AC XY: 456 AN XY: 74452

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.00966

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.00672

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Agenesis of the corpus callosum with peripheral neuropathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	11
DANN	Benign	0.81

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: rs182573709; hg19: chr15-34522410;