Variant 3-127599441-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_004526.4(MCM2):c.130C>T(p.Arg44Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as no classifications from unflagged records (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

MCM2
NM_004526.4 missense

Scores

Clinical Significance

no classifications from unflagged records no classifications from unflagged records P:1

Conservation

PhyloP100: 0.848

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 3-127599441-C-T is Pathogenic according to our data. Variant chr3-127599441-C-T is described in ClinVar as [no_classifications_from_unflagged_records]. Clinvar id is 235129.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1}. Variant chr3-127599441-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.26006913). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCM2	NM_004526.4 link	c.130C>T	p.Arg44Cys	missense_variant	2/16	ENST00000265056.12	NP_004517.2	P49736
MCM2	XM_024453531.2 link	c.103C>T	p.Arg35Cys	missense_variant	2/16		XP_024309299.1
MCM2	NR_073375.2 link	n.186C>T		non_coding_transcript_exon_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCM2	ENST00000265056.12 link	c.130C>T	p.Arg44Cys	missense_variant	2/16	1	NM_004526.4	ENSP00000265056.7		P49736

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251432

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

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

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: no classifications from unflagged records

Submissions summary: Pathogenic:1

Revision: no classifications from unflagged records

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 70

Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Feb 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;T

Eigen

Benign

0.025

Eigen_PC

Benign

0.019

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

N;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Benign

0.24

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.052

T;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MutPred

0.17

Loss of MoRF binding (P = 0.0699);.;.;

MVP

0.74

MPC

1.0

ClinPred

0.80

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.78

gMVP

0.33

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over