rs200741233

Variant names:

• chr10-77403919-G-A
• rs200741233
• NM_001161352.2:c.483C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6 BP7

The NM_001161352.2(KCNMA1):​c.483C>T​(p.Ser161Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.68
• Publications: 0 publications found

Genes affected

KCNMA1 (HGNC:6284): (potassium calcium-activated channel subfamily M alpha 1) This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]

KCNMA1 Gene-Disease associations (from GenCC):

• generalized epilepsy-paroxysmal dyskinesia syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
• Liang-Wang syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• cerebellar atrophy, developmental delay, and seizures

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.202).
• BP6: Variant 10-77403919-G-A is Benign according to our data. Variant chr10-77403919-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586096.
• BP7: Synonymous conserved (PhyloP=-2.68 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161352.2. 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
	KCNMA1	NM_001161352.2	MANE Select	c.483C>T	p.Ser161Ser	synonymous	Exon 2 of 28	NP_001154824.1	Q12791-1
	KCNMA1	NM_001437422.1		c.615C>T	p.Ser205Ser	synonymous	Exon 3 of 28	NP_001424351.1
	KCNMA1	NM_001161353.2		c.483C>T	p.Ser161Ser	synonymous	Exon 2 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.483C>T	p.Ser161Ser	synonymous	Exon 2 of 28	ENSP00000286628.8	Q12791-1
	KCNMA1	ENST00000626620.3	TSL:1	c.483C>T	p.Ser161Ser	synonymous	Exon 2 of 28	ENSP00000485867.1	Q12791-2
	KCNMA1	ENST00000639406.1	TSL:1	c.483C>T	p.Ser161Ser	synonymous	Exon 2 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000835 AC: 21 AN: 251356 AF XY: 0.000110

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.000208 AC XY: 151 AN XY: 727200

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000253 AC: 281 AN: 1111988

Other (OTH) AF: 0.000281 AC: 17 AN: 60392

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74464

African (AFR) AF: 0.0000240 AC: 1 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.000140

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Generalized epilepsy-paroxysmal dyskinesia syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.5
DANN	Benign	0.69
PhyloP100		-2.7
PromoterAI		-0.044	Neutral

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: rs200741233; hg19: chr10-79163677; COSMIC: COSV108797208; COSMIC: COSV108797208;