15-94298443-G-A

Variant summary

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

The NM_001385001.1(MCTP2):c.178G>A(p.Ala60Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,614,148 control chromosomes in the GnomAD database, including 22 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00056 (11 hom.)
• Consequence: MCTP2 NM_001385001.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.890

Genes affected

MCTP2 (HGNC:25636): (multiple C2 and transmembrane domain containing 2) Enables calcium ion binding activity. Predicted to be involved in regulation of neurotransmitter secretion. Located in cytosol and nucleoplasm. Is integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032037497).
• BP6: Variant 15-94298443-G-A is Benign according to our data. Variant chr15-94298443-G-A is described in ClinVar as [Benign]. Clinvar id is 716017.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 = 0.00526 (801/152300) while in subpopulation AFR AF= 0.0183 (761/41570). AF 95% confidence interval is 0.0172. There are 11 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCTP2	NM_001385001.1	c.178G>A	p.Ala60Thr	missense_variant	2/23	ENST00000357742.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCTP2	ENST00000357742.10	c.178G>A	p.Ala60Thr	missense_variant	2/23	1	NM_001385001.1	P1

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152182 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00127 AC: 319 AN: 251024 Hom.: 5 AF XY: 0.000907 AC XY: 123 AN XY: 135668

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.000752

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: 0.0000353

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000563 AC: 823 AN: 1461848 Hom.: 11 Cov.: 32 AF XY: 0.000492 AC XY: 358 AN XY: 727232

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152300 Hom.: 11 Cov.: 31 AF XY: 0.00507 AC XY: 378 AN XY: 74488

Gnomad4 AFR AF: 0.0183

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000898 Hom.: 3

Bravo AF: 0.00600

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00157 AC: 191

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MCTP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	15
Dann	Benign	0.77
DEOGEN2	Benign	0.0021	T;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.21	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.90	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.067
MVP		0.13
MPC		0.019
ClinPred		0.0021	T
GERP RS		3.0
Varity_R		0.047
gMVP		0.21

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: rs143256791; hg19: chr15-94841672;