10-77637553-G-A

Position:

• chr10-77637553-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000286628.14(KCNMA1):​c.90C>T​(p.His30=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000658 in 1,543,428 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (3 hom.)
• Consequence: KCNMA1 ENST00000286628.14 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.02

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-77637553-G-A is Benign according to our data. Variant chr10-77637553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-77637553-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000526 (80/152134) while in subpopulation AMR AF= 0.00105 (16/15308). AF 95% confidence interval is 0.000655. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.90C>T	p.His30=	synonymous_variant	1/28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.90C>T	p.His30=	synonymous_variant	1/28	1	NM_001161352.2	ENSP00000286628	A2

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000736

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000585 AC: 88 AN: 150326 Hom.: 1 AF XY: 0.000697 AC XY: 56 AN XY: 80376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000361

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.000178

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.000172

Gnomad NFE exome AF: 0.000619

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000672 AC: 935 AN: 1391294 Hom.: 3 Cov.: 30 AF XY: 0.000703 AC XY: 483 AN XY: 687120

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000416

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000835

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.0000677

Gnomad4 NFE exome AF: 0.000691

Gnomad4 OTH exome AF: 0.000622

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45 AN XY: 74370

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000234 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	KCNMA1: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 11, 2013

- -

Generalized epilepsy-paroxysmal dyskinesia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

- -

KCNMA1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	0.98

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

LitVar

Other links and lift over

dbSNP: rs75040504; hg19: chr10-79397311;