10-77045387-A-G

Variant names:

• chr10-77045387-A-G
• rs1247766
• NM_001161352.2:c.1750-5750T>C

Variant summary

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

The NM_001161352.2(KCNMA1):​c.1750-5750T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 152,330 control chromosomes in the GnomAD database, including 65,709 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 0.93 (65709 hom., cov: 34)
• Consequence: KCNMA1 NM_001161352.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.763
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.939 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.1750-5750T>C		intron	N/A	NP_001154824.1
	KCNMA1	NM_001437422.1		c.1882-5750T>C		intron	N/A	NP_001424351.1
	KCNMA1	NM_001161353.2		c.1750-5750T>C		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.1750-5750T>C		intron	N/A	ENSP00000286628.8
	KCNMA1	ENST00000626620.3	TSL:1	c.1750-5750T>C		intron	N/A	ENSP00000485867.1
	KCNMA1	ENST00000639406.1	TSL:1	c.1750-5750T>C		intron	N/A	ENSP00000491732.1

Frequencies

GnomAD3 genomes AF: 0.928 AC: 141315 AN: 152212 Hom.: 65665 Cov.: 34

Gnomad AFR AF: 0.947

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.928

Gnomad ASJ AF: 0.967

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.891

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.936

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

GnomAD4 genome AF: 0.928 AC: 141418 AN: 152330 Hom.: 65709 Cov.: 34 AF XY: 0.928 AC XY: 69113 AN XY: 74480

African (AFR) AF: 0.947 AC: 39385 AN: 41588

American (AMR) AF: 0.928 AC: 14201 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.967 AC: 3359 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4239 AN: 5168

South Asian (SAS) AF: 0.891 AC: 4298 AN: 4824

European-Finnish (FIN) AF: 0.932 AC: 9898 AN: 10616

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.926 AC: 62994 AN: 68036

Other (OTH) AF: 0.935 AC: 1978 AN: 2116

Alfa AF: 0.927 Hom.: 8461

Bravo AF: 0.928

Asia WGS AF: 0.852 AC: 2965 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.7
DANN	Benign	0.45
PhyloP100		0.76
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: rs1247766; hg19: chr10-78805145;