15-34230058-CAT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001365088.1(SLC12A6):c.*3821_*3822del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 442,148 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (4 hom.)
• Consequence: SLC12A6 NM_001365088.1 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.325

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 -10 ACMG points.

• BP6: Variant 15-34230058-CAT-C is Benign according to our data. Variant chr15-34230058-CAT-C is described in ClinVar as [Likely_benign]. Clinvar id is 2645147.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00393 (598/152216) while in subpopulation SAS AF= 0.00725 (35/4828). AF 95% confidence interval is 0.00536. There are 4 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC12A6	NM_001365088.1	c.*3821_*3822del		3_prime_UTR_variant	26/26	ENST00000354181.8
EMC4	NM_016454.4	c.*272_*273del		3_prime_UTR_variant	5/5	ENST00000267750.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMC4	ENST00000267750.9	c.*272_*273del		3_prime_UTR_variant	5/5	1	NM_016454.4	P1
SLC12A6	ENST00000354181.8	c.*3821_*3822del		3_prime_UTR_variant	26/26	1	NM_001365088.1	A1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152098 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00464 AC: 1346 AN: 289932 Hom.: 4 AF XY: 0.00483 AC XY: 730 AN XY: 151208

Gnomad4 AFR exome AF: 0.000660

Gnomad4 AMR exome AF: 0.00608

Gnomad4 ASJ exome AF: 0.00647

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00637

Gnomad4 FIN exome AF: 0.00254

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00437

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152216 Hom.: 4 Cov.: 33 AF XY: 0.00382 AC XY: 284 AN XY: 74422

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00725

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00543

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00389 Hom.: 0

Bravo AF: 0.00410

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

EMC4: BS2; SLC12A6: BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs539180054; hg19: chr15-34522259;