chr10-77636457-G-T

Position:

• chr10-77636457-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000480683.2(KCNMA1):​c.437C>A​(p.Pro146Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,536,206 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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: 𝑓 0.0086 (22 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (12 hom.)
• Consequence: KCNMA1 ENST00000480683.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.369

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030519068).
• BP6: Variant 10-77636457-G-T is Benign according to our data. Variant chr10-77636457-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 377217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00855 (1303/152390) while in subpopulation AFR AF= 0.0301 (1251/41600). AF 95% confidence interval is 0.0287. There are 22 homozygotes in gnomad4. There are 569 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.378+808C>A		intron_variant		ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.378+808C>A		intron_variant		1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.00853 AC: 1299 AN: 152272 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

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: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00155 AC: 208 AN: 134528 Hom.: 1 AF XY: 0.00106 AC XY: 78 AN XY: 73276

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000379

Gnomad OTH exome AF: 0.000724

GnomAD4 exome AF: 0.000763 AC: 1056 AN: 1383816 Hom.: 12 Cov.: 31 AF XY: 0.000644 AC XY: 440 AN XY: 682848

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00855 AC: 1303 AN: 152390 Hom.: 22 Cov.: 33 AF XY: 0.00763 AC XY: 569 AN XY: 74526

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.000351 Hom.: 0

Bravo AF: 0.00985

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00113 AC: 20

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.7
DANN	Benign	0.90
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0031	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
Sift4G	Uncertain	0.010	D
Polyphen		0.61	P
Vest4		0.17
MVP		0.17
GERP RS		-3.8

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: rs116144703; hg19: chr10-79396215;