NM_020708.5:c.1395-360T>C

Variant names:

• chr20-46044606-T-C
• rs4812987
• NM_020708.5:c.1395-360T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020708.5(SLC12A5):​c.1395-360T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 152,234 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.035 (181 hom., cov: 32)
• Consequence: SLC12A5 NM_020708.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• 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: Illumina, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.1395-360T>C		intron_variant	Intron 11 of 25	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.1464-360T>C		intron_variant	Intron 11 of 25		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.1395-360T>C		intron_variant	Intron 11 of 25	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5282 AN: 152116 Hom.: 177 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.0323

Gnomad SAS AF: 0.0783

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0396

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0348 AC: 5292 AN: 152234 Hom.: 181 Cov.: 32 AF XY: 0.0371 AC XY: 2759 AN XY: 74438

African (AFR) AF: 0.0186 AC: 773 AN: 41548

American (AMR) AF: 0.113 AC: 1734 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 182 AN: 3468

East Asian (EAS) AF: 0.0325 AC: 168 AN: 5164

South Asian (SAS) AF: 0.0775 AC: 373 AN: 4810

European-Finnish (FIN) AF: 0.0251 AC: 267 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0246 AC: 1673 AN: 68008

Other (OTH) AF: 0.0402 AC: 85 AN: 2116

Alfa AF: 0.0305 Hom.: 33

Bravo AF: 0.0406

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.18
DANN	Benign	0.62
PhyloP100		-1.3
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: rs4812987; hg19: chr20-44673245;