chr3-127599515-T-G

Variant names:

• chr3-127599515-T-G
• rs3087452
• NM_004526.4:c.204T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004526.4(MCM2):​c.204T>G​(p.Asp68Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,972 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (33 hom.)
• Consequence: MCM2 NM_004526.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.450
• Publications: 6 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), 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003677994).
• BP6: Variant 3-127599515-T-G is Benign according to our data. Variant chr3-127599515-T-G is described in ClinVar as Benign. ClinVar VariationId is 678700.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 = 0.0126 (1915/152248) while in subpopulation AFR AF = 0.0427 (1773/41546). AF 95% confidence interval is 0.041. There are 35 homozygotes in GnomAd4. There are 874 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1915 AD gene.

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.204T>G	p.Asp68Glu	missense	Exon 2 of 16	NP_004517.2
	MCM2	NR_073375.2		n.260T>G		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.204T>G	p.Asp68Glu	missense	Exon 2 of 16	ENSP00000265056.7	P49736
	MCM2	ENST00000927678.1		c.204T>G	p.Asp68Glu	missense	Exon 2 of 16	ENSP00000597737.1
	MCM2	ENST00000927679.1		c.204T>G	p.Asp68Glu	missense	Exon 2 of 15	ENSP00000597738.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1914 AN: 152130 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00328 AC: 824 AN: 251094 AF XY: 0.00227

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00134 AC: 1958 AN: 1461724 Hom.: 33 Cov.: 30 AF XY: 0.00113 AC XY: 825 AN XY: 727154

African (AFR) AF: 0.0442 AC: 1480 AN: 33466

American (AMR) AF: 0.00230 AC: 103 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1111942

Other (OTH) AF: 0.00343 AC: 207 AN: 60392

GnomAD4 genome AF: 0.0126 AC: 1915 AN: 152248 Hom.: 35 Cov.: 33 AF XY: 0.0117 AC XY: 874 AN XY: 74442

African (AFR) AF: 0.0427 AC: 1773 AN: 41546

American (AMR) AF: 0.00582 AC: 89 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68002

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00587 Hom.: 31

Bravo AF: 0.0142

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00408 AC: 495

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MCM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.12	N
PhyloP100		0.45
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.10
Sift	Benign	0.52	T
Sift4G	Benign	0.72	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.094		Gain of helix (P = 0.1736)
MVP		0.35
MPC		0.37
ClinPred		0.0098	T
GERP RS		2.8
PromoterAI		-0.028	Neutral
Varity_R		0.18
gMVP		0.064
Mutation Taster		=76/24	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: rs3087452; hg19: chr3-127318358;