8-66890887-C-T

Variant names:

• chr8-66890887-C-T
• rs370202367
• NM_173518.5:c.1096C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173518.5(MCMDC2):​c.1096C>T​(p.Leu366Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,608,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: MCMDC2 NM_173518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

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.1096C>T	p.Leu366Phe	missense	Exon 10 of 15	NP_775789.3
	MCMDC2	NM_001136160.2		c.1096C>T	p.Leu366Phe	missense	Exon 10 of 14	NP_001129632.1	B4DXX4
	MCMDC2	NM_001136161.2		c.1096C>T	p.Leu366Phe	missense	Exon 10 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.1096C>T	p.Leu366Phe	missense	Exon 10 of 15	ENSP00000413632.2	Q4G0Z9-1
	MCMDC2	ENST00000396592.7	TSL:1	c.1096C>T	p.Leu366Phe	missense	Exon 10 of 13	ENSP00000379837.3	Q4G0Z9-2
	MCMDC2	ENST00000872356.1		c.1042C>T	p.Leu348Phe	missense	Exon 10 of 15	ENSP00000542415.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151944 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245996 AF XY: 0.00000753

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1456624 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 724208

African (AFR) AF: 0.00 AC: 0 AN: 33212

American (AMR) AF: 0.00 AC: 0 AN: 43400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.0000593 AC: 5 AN: 84264

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1110750

Other (OTH) AF: 0.00 AC: 0 AN: 60244

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151944 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74184

African (AFR) AF: 0.00 AC: 0 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Benign	0.060	T
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.39
MPC		0.44
ClinPred		0.66	D
GERP RS		4.8
Varity_R		0.26
gMVP		0.61
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs370202367; hg19: chr8-67803122;