3-127604987-C-G

Variant names:

• chr3-127604987-C-G
• rs893293
• NM_004526.4:c.504C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004526.4(MCM2):​c.504C>G​(p.Ile168Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I168I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCM2 NM_004526.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 30 publications found

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]

MCM2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 70

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM2	NM_004526.4	c.504C>G	p.Ile168Met	missense_variant	Exon 4 of 16	ENST00000265056.12	NP_004517.2
MCM2	XM_024453531.2	c.477C>G	p.Ile159Met	missense_variant	Exon 4 of 16		XP_024309299.1
MCM2	NR_073375.2	n.579C>G		non_coding_transcript_exon_variant	Exon 4 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM2	ENST00000265056.12	c.504C>G	p.Ile168Met	missense_variant	Exon 4 of 16	1	NM_004526.4	ENSP00000265056.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 85

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 123509

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	7.0
DANN	Benign	0.97
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.24
Sift	Benign	0.31	T
Sift4G	Benign	0.28	T
Polyphen		0.85	P
Vest4		0.77
MutPred		0.30		Loss of catalytic residue at I168 (P = 0.1673);
MVP		0.74
MPC		0.87
ClinPred		0.85	D
GERP RS		-5.8
PromoterAI		-0.060	Neutral
Varity_R		0.23
gMVP		0.18
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs893293; hg19: chr3-127323830;