20-46051869-T-G

Variant names:

• chr20-46051869-T-G
• rs201525976
• NM_020708.5:c.2376T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020708.5(SLC12A5):​c.2376T>G​(p.Ile792Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I792N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC12A5 NM_020708.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001052
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.12
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37809098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5	NM_020708.5	c.2376T>G	p.Ile792Met	missense_variant, splice_region_variant	Exon 18 of 26	ENST00000243964.7	NP_065759.1
SLC12A5	NM_001134771.2	c.2445T>G	p.Ile815Met	missense_variant, splice_region_variant	Exon 18 of 26		NP_001128243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5	ENST00000243964.7	c.2376T>G	p.Ile792Met	missense_variant, splice_region_variant	Exon 18 of 26	1	NM_020708.5	ENSP00000243964.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 115374 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1092694 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 541454

African (AFR) AF: 0.00 AC: 0 AN: 21686

American (AMR) AF: 0.00 AC: 0 AN: 26728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16610

East Asian (EAS) AF: 0.00 AC: 0 AN: 14662

South Asian (SAS) AF: 0.00 AC: 0 AN: 72602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 863656

Other (OTH) AF: 0.00 AC: 0 AN: 41368

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 115374 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 52758

African (AFR) AF: 0.00 AC: 0 AN: 29690

American (AMR) AF: 0.00 AC: 0 AN: 8330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3226

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 3476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 224

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 60434

Other (OTH) AF: 0.00 AC: 0 AN: 1586

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	3.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.072	D
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		-3.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.030	D;D
Sift4G	Uncertain	0.050	T;T
Polyphen		0.21	B;P
Vest4		0.58
MutPred		0.50		Gain of MoRF binding (P = 0.0778);.;
MVP		0.81
MPC		1.9
ClinPred		0.51	D
GERP RS		-2.1
Varity_R		0.42
gMVP		0.93
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.062
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: rs201525976; hg19: chr20-44680508;