10-77636457-G-T

Variant names:

• chr10-77636457-G-T
• rs116144703
• ENST00000480683.2:c.437C>A

Variant summary

Our verdict is Benign. The variant received -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. 9/10 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
• 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)

ENSG00000293869 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000480683.2. 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.378+808C>A		intron	N/A	NP_001154824.1
	KCNMA1	NM_001322839.2		c.604C>A	p.Arg202Ser	missense	Exon 3 of 3	NP_001309768.1
	KCNMA1	NM_001271522.2		c.437C>A	p.Pro146Gln	missense	Exon 2 of 2	NP_001258451.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNMA1	ENST00000480683.2	TSL:1	c.437C>A	p.Pro146Gln	missense	Exon 2 of 2	ENSP00000474686.1
	KCNMA1	ENST00000618048.2	TSL:1	c.*286C>A		3_prime_UTR	Exon 2 of 2	ENSP00000482747.1
	KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.378+808C>A		intron	N/A	ENSP00000286628.8

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

GnomAD2 exomes AF: 0.00155 AC: 208 AN: 134528 AF XY: 0.00106

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 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

African (AFR) AF: 0.0275 AC: 870 AN: 31594

American (AMR) AF: 0.00168 AC: 60 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33890

Middle Eastern (MID) AF: 0.000527 AC: 3 AN: 5696

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078878

Other (OTH) AF: 0.00185 AC: 107 AN: 57908

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

African (AFR) AF: 0.0301 AC: 1251 AN: 41600

American (AMR) AF: 0.00274 AC: 42 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00140 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

Jul 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 28, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
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
PhyloP100		-0.37
Sift4G	Uncertain	0.010	D
Polyphen		0.61	P
Vest4		0.17
MVP		0.17
GERP RS		-3.8
Mutation Taster		=100/0	polymorphism

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: rs116144703; hg19: chr10-79396215;