NM_004526.4:c.5C>T

Variant names:

• chr3-127598471-C-T
• rs1247401070
• NM_004526.4:c.5C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004526.4(MCM2):​c.5C>T​(p.Ala2Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,184 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MCM2 NM_004526.4 missense, splice_region
• Scores: Splicing: ADA: 0.8038
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15

Genes affected

MCM2 (HGNC:6944): (minichromosome maintenance complex component 2) The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Oct 2012]

TPRA1 (HGNC:30413): (transmembrane protein adipocyte associated 1) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Predicted to act upstream of or within embryonic cleavage and negative regulation of mitotic cell cycle phase transition. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity MCM2_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM2	NM_004526.4	c.5C>T	p.Ala2Val	missense_variant, splice_region_variant	Exon 1 of 16	ENST00000265056.12	NP_004517.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM2	ENST00000265056.12	c.5C>T	p.Ala2Val	missense_variant, splice_region_variant	Exon 1 of 16	1	NM_004526.4	ENSP00000265056.7
MCM2	ENST00000474964.5	n.5C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 16	2		ENSP00000420007.1
TPRA1	ENST00000648957.1	c.-1062G>A		upstream_gene_variant				ENSP00000498161.1
TPRA1	ENST00000490643.5	c.-488G>A		upstream_gene_variant		5		ENSP00000419822.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.23		Loss of catalytic residue at M1 (P = 0.0257);
MVP		0.48
MPC		0.48
ClinPred		0.85	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.21
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1247401070; hg19: chr3-127317314;