5-94710819-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024717.7(MCTP1):c.2829G>C(p.Trp943Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCTP1 NM_024717.7 missense, splice_region
• Scores: Splicing: ADA: 0.9945
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

MCTP1 (HGNC:26183): (multiple C2 and transmembrane domain containing 1) Enables calcium ion binding activity. Predicted to be involved in several processes, including modulation of chemical synaptic transmission; negative regulation of endocytosis; and negative regulation of response to oxidative stress. Is integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLF1 (HGNC:25408): (SMC5-SMC6 complex localization factor 1) Enables ubiquitin protein ligase binding activity. Involved in several processes, including positive regulation of cellular component organization; positive regulation of double-strand break repair; and protein localization to site of double-strand break. Located in nucleoplasm and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCTP1	NM_024717.7	c.2829G>C	p.Trp943Cys	missense_variant, splice_region_variant	21/23	ENST00000515393.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCTP1	ENST00000515393.6	c.2829G>C	p.Trp943Cys	missense_variant, splice_region_variant	21/23	1	NM_024717.7	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.2829G>C (p.W943C) alteration is located in exon 21 (coding exon 21) of the MCTP1 gene. This alteration results from a G to C substitution at nucleotide position 2829, causing the tryptophan (W) at amino acid position 943 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.;.;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-11	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.
Polyphen		1.0	D;D;.;D;.
Vest4		0.95
MutPred		0.61		Loss of catalytic residue at L941 (P = 0.0268);.;.;.;.;
MVP		0.73
MPC		1.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-94046524;