rs35583475

Variant names:

• chr15-34254503-G-A
• rs35583475
• NM_001365088.1:c.963C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-34254503-G-A
• chr15-34254503-G-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.963C>T​(p.Tyr321Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,612,878 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (43 hom., cov: 32)
  • Exomes 𝑓: 0.017 (388 hom.)
• Consequence: SLC12A6 NM_001365088.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.594
• Publications: 4 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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Orphanet
• Charcot-Marie-Tooth disease, axonal, IIa 2II

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 15-34254503-G-A is Benign according to our data. Variant chr15-34254503-G-A is described in ClinVar as Benign. ClinVar VariationId is 139118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.594 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0714 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	NM_001365088.1	MANE Select	c.963C>T	p.Tyr321Tyr	synonymous	Exon 9 of 26	NP_001352017.1	Q9UHW9-1
	SLC12A6	NM_133647.2		c.963C>T	p.Tyr321Tyr	synonymous	Exon 8 of 25	NP_598408.1	Q9UHW9-1
	SLC12A6	NM_001042496.2		c.936C>T	p.Tyr312Tyr	synonymous	Exon 9 of 26	NP_001035961.1	Q9UHW9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.963C>T	p.Tyr321Tyr	synonymous	Exon 9 of 26	ENSP00000346112.3	Q9UHW9-1
	SLC12A6	ENST00000560611.5	TSL:1	c.963C>T	p.Tyr321Tyr	synonymous	Exon 8 of 25	ENSP00000454168.1	Q9UHW9-1
	SLC12A6	ENST00000558589.5	TSL:1	c.936C>T	p.Tyr312Tyr	synonymous	Exon 9 of 26	ENSP00000452776.1	Q9UHW9-4

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2549 AN: 152148 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0257 AC: 6451 AN: 251396 AF XY: 0.0231

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0798

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0127

Gnomad FIN exome AF: 0.0702

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0169 AC: 24715 AN: 1460612 Hom.: 388 Cov.: 31 AF XY: 0.0163 AC XY: 11812 AN XY: 726744

African (AFR) AF: 0.00221 AC: 74 AN: 33452

American (AMR) AF: 0.0735 AC: 3288 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26130

East Asian (EAS) AF: 0.0124 AC: 491 AN: 39696

South Asian (SAS) AF: 0.00161 AC: 139 AN: 86228

European-Finnish (FIN) AF: 0.0654 AC: 3492 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0146 AC: 16174 AN: 1110870

Other (OTH) AF: 0.0170 AC: 1028 AN: 60346

GnomAD4 genome AF: 0.0168 AC: 2555 AN: 152266 Hom.: 43 Cov.: 32 AF XY: 0.0192 AC XY: 1431 AN XY: 74446

African (AFR) AF: 0.00402 AC: 167 AN: 41566

American (AMR) AF: 0.0359 AC: 549 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.0712 AC: 754 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 990 AN: 68022

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0150 Hom.: 64

Bravo AF: 0.0161

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0120

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Agenesis of the corpus callosum with peripheral neuropathy (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.2
DANN	Benign	0.87
PhyloP100		0.59
Mutation Taster		=99/1	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: rs35583475; hg19: chr15-34546704;