Genetic Variant NM_173518.5:c.875C>A (chr8-66883796-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173518.5(MCMDC2):c.875C>A(p.Ser292Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,318 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S292C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MCMDC2
NM_173518.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.95

Publications

1 publications found

Variant links:

Genes affected

MCMDC2 (HGNC:26368): (minichromosome maintenance domain containing 2) Predicted to enable ATP binding activity and DNA binding activity. Predicted to be involved in double-strand break repair via break-induced replication. Predicted to act upstream of or within gamete generation and meiosis I cell cycle process. [provided by Alliance of Genome Resources, Apr 2022]

MCMDC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173518.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCMDC2	NM_173518.5	MANE Select	c.875C>A	p.Ser292Tyr	missense	Exon 9 of 15	NP_775789.3
MCMDC2	NM_001136160.2		c.875C>A	p.Ser292Tyr	missense	Exon 9 of 14	NP_001129632.1	B4DXX4
MCMDC2	NM_001136161.2		c.875C>A	p.Ser292Tyr	missense	Exon 9 of 13	NP_001129633.1	Q4G0Z9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCMDC2	ENST00000422365.7	TSL:2 MANE Select	c.875C>A	p.Ser292Tyr	missense	Exon 9 of 15	ENSP00000413632.2	Q4G0Z9-1
MCMDC2	ENST00000396592.7	TSL:1	c.875C>A	p.Ser292Tyr	missense	Exon 9 of 13	ENSP00000379837.3	Q4G0Z9-2
MCMDC2	ENST00000492775.5	TSL:1	c.875C>A	p.Ser292Tyr	missense	Exon 9 of 9	ENSP00000428037.1	G3XAN3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461024

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726816

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111604

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.3

PhyloP100

4.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.7

REVEL

Benign

0.24

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.014

Polyphen

0.99

Vest4

0.64

MutPred

0.72

Gain of helix (P = 0.0325)

MVP

0.49

MPC

0.44

ClinPred

0.96

GERP RS

4.9

Varity_R

0.22

gMVP

0.50

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over