8-66883796-C-T

Variant names:

• chr8-66883796-C-T
• rs377744254
• NM_173518.5:c.875C>T

Variant summary

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

The NM_173518.5(MCMDC2):​c.875C>T​(p.Ser292Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,024 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MCMDC2 NM_173518.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.95
• Publications: 0 publications found

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]

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCMDC2	NM_173518.5	MANE Select	c.875C>T	p.Ser292Phe	missense	Exon 9 of 15	NP_775789.3
	MCMDC2	NM_001136160.2		c.875C>T	p.Ser292Phe	missense	Exon 9 of 14	NP_001129632.1	B4DXX4
	MCMDC2	NM_001136161.2		c.875C>T	p.Ser292Phe	missense	Exon 9 of 13	NP_001129633.1	Q4G0Z9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCMDC2	ENST00000422365.7	TSL:2 MANE Select	c.875C>T	p.Ser292Phe	missense	Exon 9 of 15	ENSP00000413632.2	Q4G0Z9-1
	MCMDC2	ENST00000396592.7	TSL:1	c.875C>T	p.Ser292Phe	missense	Exon 9 of 13	ENSP00000379837.3	Q4G0Z9-2
	MCMDC2	ENST00000492775.5	TSL:1	c.875C>T	p.Ser292Phe	missense	Exon 9 of 9	ENSP00000428037.1	G3XAN3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461024 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726816

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111604

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0094	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.013	D
Polyphen		0.93	P
Vest4		0.70
MutPred		0.74		Loss of catalytic residue at S292 (P = 0.0226)
MVP		0.47
MPC		0.38
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.20
gMVP		0.46
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs377744254; hg19: chr8-67796031;