rs74010036

Variant names:

• chr15-34245416-G-A
• rs74010036
• NM_001365088.1:c.1825-13C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_133647.2(SLC12A6):​c.1825-13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,441,302 control chromosomes in the GnomAD database, including 10,102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (894 hom., cov: 32)
  • Exomes 𝑓: 0.12 (9208 hom.)
• Consequence: SLC12A6 NM_133647.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.228
• Publications: 5 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)

LOC124903461 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-34245416-G-A is Benign according to our data. Variant chr15-34245416-G-A is described in ClinVar as Benign. ClinVar VariationId is 159889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133647.2. 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.1825-13C>T		intron	N/A	NP_001352017.1
	SLC12A6	NM_133647.2		c.1825-13C>T		intron	N/A	NP_598408.1
	SLC12A6	NM_001042496.2		c.1798-13C>T		intron	N/A	NP_001035961.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A6	ENST00000354181.8	TSL:1 MANE Select	c.1825-13C>T		intron	N/A	ENSP00000346112.3
	SLC12A6	ENST00000560611.5	TSL:1	c.1825-13C>T		intron	N/A	ENSP00000454168.1
	SLC12A6	ENST00000558589.5	TSL:1	c.1798-13C>T		intron	N/A	ENSP00000452776.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15571 AN: 152086 Hom.: 895 Cov.: 32

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0748

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0837

GnomAD2 exomes AF: 0.106 AC: 26682 AN: 251330 AF XY: 0.110

Gnomad AFR exome AF: 0.0769

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.0225

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.117 AC: 150571 AN: 1289098 Hom.: 9208 Cov.: 19 AF XY: 0.118 AC XY: 76718 AN XY: 650570

African (AFR) AF: 0.0783 AC: 2357 AN: 30120

American (AMR) AF: 0.0766 AC: 3410 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3480 AN: 25060

East Asian (EAS) AF: 0.0159 AC: 620 AN: 38912

South Asian (SAS) AF: 0.149 AC: 12377 AN: 82878

European-Finnish (FIN) AF: 0.103 AC: 5505 AN: 53346

Middle Eastern (MID) AF: 0.143 AC: 785 AN: 5472

European-Non Finnish (NFE) AF: 0.121 AC: 115712 AN: 954270

Other (OTH) AF: 0.116 AC: 6325 AN: 54514

GnomAD4 genome AF: 0.102 AC: 15574 AN: 152204 Hom.: 894 Cov.: 32 AF XY: 0.102 AC XY: 7570 AN XY: 74402

African (AFR) AF: 0.0783 AC: 3252 AN: 41550

American (AMR) AF: 0.0747 AC: 1142 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3472

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5186

South Asian (SAS) AF: 0.153 AC: 735 AN: 4816

European-Finnish (FIN) AF: 0.111 AC: 1174 AN: 10580

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8314 AN: 67998

Other (OTH) AF: 0.0843 AC: 178 AN: 2112

Alfa AF: 0.121 Hom.: 459

Bravo AF: 0.0963

Asia WGS AF: 0.0820 AC: 284 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.5
DANN	Benign	0.32
PhyloP100		0.23
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: rs74010036; hg19: chr15-34537617;