Genetic Variant KCNMA1:p.Pro146Arg (chr10-77636457-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000480683.2(KCNMA1):c.437C>G(p.Pro146Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/11 in silico tools predict a benign outcome for this variant. 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. P146L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

KCNMA1
ENST00000480683.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.369

Publications

0 publications found

Variant links:

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)

KCNMA1 links:

ENSG00000293869 (HGNC:):

ENSG00000293869 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05838445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2 link	c.378+808C>G		intron_variant	Intron 1 of 27	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14 link	c.378+808C>G		intron_variant	Intron 1 of 27	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1383816

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

682848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31594

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078878

Other (OTH)

AF:

0.00

AC:

AN:

57908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

5.6

(source)

DANN

Benign

0.82

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.23

M_CAP

Benign

0.0091

MetaRNN

Benign

0.058

PhyloP100

-0.37

Sift4G

Uncertain

0.010

Vest4

0.097

GERP RS

-3.8

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over