15-34230126-A-G

Variant names:

• chr15-34230126-A-G
• rs557606663
• NM_001365088.1:c.*3755T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001365088.1(SLC12A6):​c.*3755T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000238 in 293,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: SLC12A6 NM_001365088.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05
• Publications: 0 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]

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365088.1. 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.*3755T>C		3_prime_UTR	Exon 26 of 26	NP_001352017.1	Q9UHW9-1
	EMC4	NM_016454.4	MANE Select	c.*338A>G		3_prime_UTR	Exon 5 of 5	NP_057538.1	Q5J8M3-1
	SLC12A6	NM_133647.2		c.*3755T>C		3_prime_UTR	Exon 25 of 25	NP_598408.1	Q9UHW9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.*3755T>C		3_prime_UTR	Exon 26 of 26	ENSP00000346112.3	Q9UHW9-1
	EMC4	ENST00000267750.9	TSL:1 MANE Select	c.*338A>G		3_prime_UTR	Exon 5 of 5	ENSP00000267750.4	Q5J8M3-1
	SLC12A6	ENST00000290209.9	TSL:1	c.*3755T>C		3_prime_UTR	Exon 25 of 25	ENSP00000290209.5	Q9UHW9-2

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000212 AC: 30 AN: 141620 Hom.: 0 Cov.: 0 AF XY: 0.000205 AC XY: 15 AN XY: 73094

African (AFR) AF: 0.00 AC: 0 AN: 4490

American (AMR) AF: 0.000202 AC: 1 AN: 4958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5464

East Asian (EAS) AF: 0.00 AC: 0 AN: 10692

South Asian (SAS) AF: 0.00 AC: 0 AN: 6262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 758

European-Non Finnish (NFE) AF: 0.000304 AC: 28 AN: 92010

Other (OTH) AF: 0.000106 AC: 1 AN: 9434

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74506

African (AFR) AF: 0.0000481 AC: 2 AN: 41600

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000276

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Agenesis of the corpus callosum with peripheral neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.89
PhyloP100		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs557606663; hg19: chr15-34522327;