22-39570772-C-T

Position:

• chr22-39570772-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BA1

The ENST00000402142.4(CACNA1I):​c.20C>T​(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,608,158 control chromosomes in the GnomAD database, including 494 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.031 (264 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (230 hom.)
• Consequence: CACNA1I ENST00000402142.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0490

Genes affected

CACNA1I (HGNC:1396): (calcium voltage-gated channel subunit alpha1 I) This gene encodes the pore-forming alpha subunit of a voltage gated calcium channel. The encoded protein is a member of a subfamily of calcium channels referred to as is a low voltage-activated, T-type, calcium channel. The channel encoded by this protein is characterized by a slower activation and inactivation compared to other T-type calcium channels. This protein may be involved in calcium signaling in neurons. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1I. . Gene score misZ 5.0511 (greater than the threshold 3.09). Trascript score misZ 3.2896 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, neurodevelopmental disorder with speech impairment and with or without seizures.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016570389).
• BP6: Variant 22-39570772-C-T is Benign according to our data. Variant chr22-39570772-C-T is described in ClinVar as [Benign]. Clinvar id is 3055495.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1I	NM_021096.4	c.20C>T	p.Pro7Leu	missense_variant	1/37	ENST00000402142.4	NP_066919.2
CACNA1I	NM_001003406.2	c.20C>T	p.Pro7Leu	missense_variant	1/36		NP_001003406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1I	ENST00000402142.4	c.20C>T	p.Pro7Leu	missense_variant	1/37	1	NM_021096.4	ENSP00000385019	A2
CACNA1I	ENST00000404898.5	c.20C>T	p.Pro7Leu	missense_variant	1/36	1		ENSP00000384093	A2
CACNA1I	ENST00000401624.5	c.20C>T	p.Pro7Leu	missense_variant	1/36	1		ENSP00000383887	P4
CACNA1I	ENST00000407673.5	c.20C>T	p.Pro7Leu	missense_variant	1/35	1		ENSP00000385680	A2

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4700 AN: 152108 Hom.: 262 Cov.: 31

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

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: 0.000603

Gnomad OTH AF: 0.0173

GnomAD3 exomes AF: 0.00746 AC: 1745 AN: 234048 Hom.: 79 AF XY: 0.00602 AC XY: 771 AN XY: 128026

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000268

Gnomad FIN exome AF: 0.0000968

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.00260

GnomAD4 exome AF: 0.00334 AC: 4862 AN: 1455932 Hom.: 230 Cov.: 31 AF XY: 0.00294 AC XY: 2125 AN XY: 724004

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.00459

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000315

Gnomad4 FIN exome AF: 0.0000575

Gnomad4 NFE exome AF: 0.000406

Gnomad4 OTH exome AF: 0.00707

GnomAD4 genome AF: 0.0310 AC: 4720 AN: 152226 Hom.: 264 Cov.: 31 AF XY: 0.0295 AC XY: 2199 AN XY: 74422

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0103 Hom.: 48

Bravo AF: 0.0353

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0984 AC: 418

ESP6500EA AF: 0.000475 AC: 4

ExAC AF: 0.00933 AC: 1128

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CACNA1I-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

This variant is classified as 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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.025	.;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.55	T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0010	.;.;B;B
Vest4		0.11
MVP		0.30
MPC		0.77
ClinPred		0.0015	T
GERP RS		-2.5
Varity_R		0.036
gMVP		0.38

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: rs60192012; hg19: chr22-39966777;