NM_001365088.1:c.3003C>T

Variant names:

• chr15-34236747-G-A
• rs4577050
• NM_001365088.1:c.3003C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365088.1(SLC12A6):​c.3003C>T​(p.Leu1001Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.667 in 1,607,134 control chromosomes in the GnomAD database, including 360,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (29337 hom., cov: 32)
  • Exomes 𝑓: 0.67 (331296 hom.)
• Consequence: SLC12A6 NM_001365088.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.156
• Publications: 26 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]

SLC12A6 Gene-Disease associations (from GenCC):

• agenesis of the corpus callosum with peripheral neuropathy

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease, axonal, IIa 2II

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 15-34236747-G-A is Benign according to our data. Variant chr15-34236747-G-A is described in ClinVar as Benign. ClinVar VariationId is 159896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.156 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	NM_001365088.1	MANE Select	c.3003C>T	p.Leu1001Leu	synonymous	Exon 23 of 26	NP_001352017.1
	SLC12A6	NM_133647.2		c.3003C>T	p.Leu1001Leu	synonymous	Exon 22 of 25	NP_598408.1
	SLC12A6	NM_001042496.2		c.2976C>T	p.Leu992Leu	synonymous	Exon 23 of 26	NP_001035961.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.3003C>T	p.Leu1001Leu	synonymous	Exon 23 of 26	ENSP00000346112.3
	SLC12A6	ENST00000560611.5	TSL:1	c.3003C>T	p.Leu1001Leu	synonymous	Exon 22 of 25	ENSP00000454168.1
	SLC12A6	ENST00000558589.5	TSL:1	c.2976C>T	p.Leu992Leu	synonymous	Exon 23 of 26	ENSP00000452776.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92826 AN: 151918 Hom.: 29338 Cov.: 32

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.671

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.640

GnomAD2 exomes AF: 0.658 AC: 165521 AN: 251420 AF XY: 0.660

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.702

Gnomad ASJ exome AF: 0.624

Gnomad EAS exome AF: 0.675

Gnomad FIN exome AF: 0.716

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.650

GnomAD4 exome AF: 0.673 AC: 978619 AN: 1455098 Hom.: 331296 Cov.: 32 AF XY: 0.671 AC XY: 485974 AN XY: 724248

African (AFR) AF: 0.413 AC: 13788 AN: 33362

American (AMR) AF: 0.698 AC: 31219 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16247 AN: 26086

East Asian (EAS) AF: 0.721 AC: 28610 AN: 39670

South Asian (SAS) AF: 0.609 AC: 52389 AN: 86082

European-Finnish (FIN) AF: 0.709 AC: 37886 AN: 53402

Middle Eastern (MID) AF: 0.513 AC: 2956 AN: 5760

European-Non Finnish (NFE) AF: 0.684 AC: 756415 AN: 1105884

Other (OTH) AF: 0.650 AC: 39109 AN: 60136

GnomAD4 genome AF: 0.611 AC: 92866 AN: 152036 Hom.: 29337 Cov.: 32 AF XY: 0.614 AC XY: 45631 AN XY: 74306

African (AFR) AF: 0.432 AC: 17908 AN: 41420

American (AMR) AF: 0.690 AC: 10538 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2178 AN: 3468

East Asian (EAS) AF: 0.671 AC: 3472 AN: 5174

South Asian (SAS) AF: 0.603 AC: 2905 AN: 4816

European-Finnish (FIN) AF: 0.715 AC: 7560 AN: 10574

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.681 AC: 46290 AN: 67988

Other (OTH) AF: 0.641 AC: 1352 AN: 2110

Alfa AF: 0.654 Hom.: 49400

Bravo AF: 0.602

Asia WGS AF: 0.637 AC: 2215 AN: 3478

EpiCase AF: 0.673

EpiControl AF: 0.671

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Agenesis of the corpus callosum with peripheral neuropathy (4)
-	-	4	not provided (4)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.0
DANN	Benign	0.74
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs4577050; hg19: chr15-34528948; COSMIC: COSV51626112; COSMIC: COSV51626112;