10-77256181-T-C

Variant names:

• chr10-77256181-T-C
• rs555766
• NM_001161352.2:c.541-4925A>G

Variant summary

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

The NM_001161352.2(KCNMA1):​c.541-4925A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 152,094 control chromosomes in the GnomAD database, including 45,521 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 0.77 (45521 hom., cov: 32)
• Consequence: KCNMA1 NM_001161352.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• Publications: 8 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: Illumina, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• Liang-Wang syndrome

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	NM_001161352.2	MANE Select	c.541-4925A>G		intron	N/A	NP_001154824.1
	KCNMA1	NM_001437422.1		c.673-4925A>G		intron	N/A	NP_001424351.1
	KCNMA1	NM_001161353.2		c.541-4925A>G		intron	N/A	NP_001154825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.541-4925A>G		intron	N/A	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.541-4925A>G		intron	N/A	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.541-4925A>G		intron	N/A	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.769 AC: 116817 AN: 151976 Hom.: 45475 Cov.: 32

Gnomad AFR AF: 0.868

Gnomad AMI AF: 0.772

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.963

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.693

Gnomad OTH AF: 0.767

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

GnomAD4 genome AF: 0.769 AC: 116920 AN: 152094 Hom.: 45521 Cov.: 32 AF XY: 0.768 AC XY: 57099 AN XY: 74342

African (AFR) AF: 0.868 AC: 36028 AN: 41518

American (AMR) AF: 0.816 AC: 12467 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2780 AN: 3470

East Asian (EAS) AF: 0.963 AC: 4976 AN: 5166

South Asian (SAS) AF: 0.828 AC: 3994 AN: 4824

European-Finnish (FIN) AF: 0.667 AC: 7038 AN: 10556

Middle Eastern (MID) AF: 0.767 AC: 224 AN: 292

European-Non Finnish (NFE) AF: 0.693 AC: 47086 AN: 67976

Other (OTH) AF: 0.770 AC: 1623 AN: 2108

Alfa AF: 0.725 Hom.: 157342

Bravo AF: 0.786

Asia WGS AF: 0.911 AC: 3167 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.1
DANN	Benign	0.59
PhyloP100		-0.0090
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: rs555766; hg19: chr10-79015939;