rs1444746944

Variant names:

• chr3-127599359-G-T
• rs1444746944
• NM_004526.4:c.48G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004526.4(MCM2):​c.48G>T​(p.Gln16His) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q16R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCM2 NM_004526.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0360
• Publications: 0 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058360904).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004526.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM2	NM_004526.4	MANE Select	c.48G>T	p.Gln16His	missense	Exon 2 of 16	NP_004517.2
	MCM2	NR_073375.2		n.104G>T		non_coding_transcript_exon	Exon 2 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCM2	ENST00000265056.12	TSL:1 MANE Select	c.48G>T	p.Gln16His	missense	Exon 2 of 16	ENSP00000265056.7	P49736
	MCM2	ENST00000927678.1		c.48G>T	p.Gln16His	missense	Exon 2 of 16	ENSP00000597737.1
	MCM2	ENST00000927679.1		c.48G>T	p.Gln16His	missense	Exon 2 of 15	ENSP00000597738.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.1
DANN	Benign	0.93
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.036
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.042
Sift	Benign	0.35	T
Sift4G	Benign	0.13	T
Polyphen		0.015	B
Vest4		0.13
MutPred		0.15		Gain of catalytic residue at Q16 (P = 0.0526)
MVP		0.51
MPC		0.42
ClinPred		0.074	T
GERP RS		-4.8
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.036
gMVP		0.25
Mutation Taster		=100/0	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: rs1444746944; hg19: chr3-127318202;