rs2297198

Variant names:

• chr20-46045644-C-T
• rs2297198
• NM_020708.5:c.1570-234C>T

Variant summary

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

The NM_020708.5(SLC12A5):​c.1570-234C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 152,070 control chromosomes in the GnomAD database, including 2,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (2245 hom., cov: 32)
• Consequence: SLC12A5 NM_020708.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.556
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 20-46045644-C-T is Benign according to our data. Variant chr20-46045644-C-T is described in ClinVar as Benign. ClinVar VariationId is 1278132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.1570-234C>T		intron_variant	Intron 12 of 25	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.1639-234C>T		intron_variant	Intron 12 of 25		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.1570-234C>T		intron_variant	Intron 12 of 25	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23293 AN: 151950 Hom.: 2245 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.153 AC: 23287 AN: 152070 Hom.: 2245 Cov.: 32 AF XY: 0.156 AC XY: 11600 AN XY: 74334

African (AFR) AF: 0.0364 AC: 1511 AN: 41508

American (AMR) AF: 0.142 AC: 2176 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 795 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1620 AN: 5142

South Asian (SAS) AF: 0.192 AC: 925 AN: 4814

European-Finnish (FIN) AF: 0.192 AC: 2027 AN: 10580

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13612 AN: 67942

Other (OTH) AF: 0.164 AC: 347 AN: 2116

Alfa AF: 0.178 Hom.: 5204

Bravo AF: 0.146

Asia WGS AF: 0.196 AC: 684 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2297198; hg19: chr20-44674283;