Genetic Variant NM_001161352.2:c.1320C>T (chr10-77090414-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4BP6_Very_StrongBP7BS1BS2

The NM_001161352.2(KCNMA1):c.1320C>T(p.Ile440Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,610,452 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 3 hom. )

Consequence

KCNMA1
NM_001161352.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.132

Publications

5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Illumina
Liang-Wang syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
cerebellar atrophy, developmental delay, and seizures
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

KCNMA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.264).

BP6

Variant 10-77090414-G-A is Benign according to our data. Variant chr10-77090414-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 289603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.132 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00146 (222/152236) while in subpopulation NFE AF = 0.00241 (164/68020). AF 95% confidence interval is 0.00211. There are 1 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNMA1	NM_001161352.2	MANE Select	c.1320C>T	p.Ile440Ile	synonymous	Exon 10 of 28	NP_001154824.1	Q12791-1
KCNMA1	NM_001437422.1		c.1452C>T	p.Ile484Ile	synonymous	Exon 11 of 28	NP_001424351.1
KCNMA1	NM_001161353.2		c.1320C>T	p.Ile440Ile	synonymous	Exon 10 of 28	NP_001154825.1	Q12791-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNMA1	ENST00000286628.14	TSL:1 MANE Select	c.1320C>T	p.Ile440Ile	synonymous	Exon 10 of 28	ENSP00000286628.8	Q12791-1
KCNMA1	ENST00000626620.3	TSL:1	c.1320C>T	p.Ile440Ile	synonymous	Exon 10 of 28	ENSP00000485867.1	Q12791-2
KCNMA1	ENST00000639406.1	TSL:1	c.1320C>T	p.Ile440Ile	synonymous	Exon 10 of 29	ENSP00000491732.1	B7ZMF5

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

222

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00198

AC:

497

AN:

251288

AF XY:

0.00210

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00332

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00203

AC:

2966

AN:

1458216

Hom.:

Cov.:

AF XY:

0.00202

AC XY:

1466

AN XY:

725718

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33404

American (AMR)

AF:

0.000134

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26108

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00183

AC:

158

AN:

86158

European-Finnish (FIN)

AF:

0.00212

AC:

113

AN:

53414

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00230

AC:

2549

AN:

1108682

Other (OTH)

AF:

0.00184

AC:

111

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

151

302

454

605

756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

176

264

352

440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00146

AC:

222

AN:

152236

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41540

American (AMR)

AF:

0.000458

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00241

AC:

164

AN:

68020

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00117

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00243

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Generalized epilepsy-paroxysmal dyskinesia syndrome (4)

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.8

(source)

DANN

Benign

0.76

PhyloP100

0.13

PromoterAI

-0.011

Neutral

(source)

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over