20-46023148-C-T

Variant names:

• chr20-46023148-C-T
• rs12479993
• NM_001134771.2:c.121+1262C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001134771.2(SLC12A5):​c.121+1262C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 398,070 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (174 hom., cov: 32)
  • Exomes 𝑓: 0.029 (171 hom.)
• Consequence: SLC12A5 NM_001134771.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.199
• Publications: 2 publications found

Genes affected

SLC12A5 (HGNC:13818): (solute carrier family 12 member 5) K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]

SLC12A5 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 34

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• epilepsy of infancy with migrating focal seizures

  Inheritance: AR Classification: STRONG Submitted by: G2P
• malignant migrating partial seizures of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epilepsy, idiopathic generalized, susceptibility to, 14

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Illumina
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-46023148-C-T is Benign according to our data. Variant chr20-46023148-C-T is described in ClinVar as Benign. ClinVar VariationId is 3255309.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134771.2. 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
	SLC12A5	NM_001134771.2		c.121+1262C>T		intron	N/A	NP_001128243.1	Q9H2X9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC12A5	ENST00000454036.6	TSL:5	c.121+1262C>T		intron	N/A	ENSP00000387694.1	Q9H2X9-1
	SLC12A5	ENST00000626701.1	TSL:3	c.350+77C>T		intron	N/A	ENSP00000487372.1	A0A0D9SGD0
	SLC12A5	ENST00000413737.2	TSL:3	c.188+77C>T		intron	N/A	ENSP00000487291.1	A0A0D9SGA5

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4411 AN: 152086 Hom.: 171 Cov.: 32

Gnomad AFR AF: 0.00780

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.0299

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0330

GnomAD4 exome AF: 0.0294 AC: 7218 AN: 245866 Hom.: 171 Cov.: 0 AF XY: 0.0291 AC XY: 3631 AN XY: 124580

African (AFR) AF: 0.00766 AC: 55 AN: 7182

American (AMR) AF: 0.144 AC: 1070 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 482 AN: 9240

East Asian (EAS) AF: 0.0475 AC: 1087 AN: 22896

South Asian (SAS) AF: 0.0318 AC: 81 AN: 2544

European-Finnish (FIN) AF: 0.0178 AC: 371 AN: 20810

Middle Eastern (MID) AF: 0.0209 AC: 27 AN: 1292

European-Non Finnish (NFE) AF: 0.0218 AC: 3451 AN: 158096

Other (OTH) AF: 0.0363 AC: 594 AN: 16372

GnomAD4 genome AF: 0.0290 AC: 4417 AN: 152204 Hom.: 174 Cov.: 32 AF XY: 0.0310 AC XY: 2310 AN XY: 74420

African (AFR) AF: 0.00777 AC: 323 AN: 41546

American (AMR) AF: 0.119 AC: 1815 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3468

East Asian (EAS) AF: 0.0298 AC: 154 AN: 5174

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4820

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0217 AC: 1478 AN: 67984

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0231 Hom.: 11

Bravo AF: 0.0354

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.3
DANN	Benign	0.86
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12479993; hg19: chr20-44651787;