chr15-34230039-C-A

Variant names:

• chr15-34230039-C-A
• rs552491692
• NM_001365088.1:c.*3842G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001365088.1(SLC12A6):​c.*3842G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 460,980 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 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: SLC12A6 NM_001365088.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000657 (100/152118) while in subpopulation AMR AF = 0.00131 (20/15268). AF 95% confidence interval is 0.000867. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*3842G>T		3_prime_UTR	Exon 26 of 26	NP_001352017.1	Q9UHW9-1
	EMC4	NM_016454.4	MANE Select	c.*251C>A		3_prime_UTR	Exon 5 of 5	NP_057538.1	Q5J8M3-1
	SLC12A6	NM_133647.2		c.*3842G>T		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.*3842G>T		3_prime_UTR	Exon 26 of 26	ENSP00000346112.3	Q9UHW9-1
	EMC4	ENST00000267750.9	TSL:1 MANE Select	c.*251C>A		3_prime_UTR	Exon 5 of 5	ENSP00000267750.4	Q5J8M3-1
	SLC12A6	ENST00000290209.9	TSL:1	c.*3842G>T		3_prime_UTR	Exon 25 of 25	ENSP00000290209.5	Q9UHW9-2

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152000 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000414 AC: 128 AN: 308862 Hom.: 0 Cov.: 0 AF XY: 0.000447 AC XY: 72 AN XY: 161178

African (AFR) AF: 0.00111 AC: 9 AN: 8082

American (AMR) AF: 0.00148 AC: 15 AN: 10120

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 22 AN: 10472

East Asian (EAS) AF: 0.00 AC: 0 AN: 24044

South Asian (SAS) AF: 0.00 AC: 0 AN: 18796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22878

Middle Eastern (MID) AF: 0.00267 AC: 4 AN: 1500

European-Non Finnish (NFE) AF: 0.000258 AC: 50 AN: 193812

Other (OTH) AF: 0.00146 AC: 28 AN: 19158

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74368

African (AFR) AF: 0.000987 AC: 41 AN: 41524

American (AMR) AF: 0.00131 AC: 20 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67968

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000903

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	-0.30
CADD	Benign	16
DANN	Benign	0.82
PhyloP100		2.3

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: rs552491692; hg19: chr15-34522240;