8-66878585-A-T

Variant names:

• chr8-66878585-A-T
• rs200037793
• NM_173518.5:c.493A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173518.5(MCMDC2):​c.493A>T​(p.Ile165Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,426,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MCMDC2 NM_173518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2585613).

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.493A>T	p.Ile165Leu	missense	Exon 6 of 15	NP_775789.3
	MCMDC2	NM_001136160.2		c.493A>T	p.Ile165Leu	missense	Exon 6 of 14	NP_001129632.1	B4DXX4
	MCMDC2	NM_001136161.2		c.493A>T	p.Ile165Leu	missense	Exon 6 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.493A>T	p.Ile165Leu	missense	Exon 6 of 15	ENSP00000413632.2	Q4G0Z9-1
	MCMDC2	ENST00000396592.7	TSL:1	c.493A>T	p.Ile165Leu	missense	Exon 6 of 13	ENSP00000379837.3	Q4G0Z9-2
	MCMDC2	ENST00000492775.5	TSL:1	c.493A>T	p.Ile165Leu	missense	Exon 6 of 9	ENSP00000428037.1	G3XAN3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426622 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 708096

African (AFR) AF: 0.00 AC: 0 AN: 31990

American (AMR) AF: 0.00 AC: 0 AN: 38164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 38324

South Asian (SAS) AF: 0.00 AC: 0 AN: 76682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099048

Other (OTH) AF: 0.0000170 AC: 1 AN: 58852

GnomAD4 genome Cov.: 32

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	0.29
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.025	D
Polyphen		0.55	P
Vest4		0.48
MutPred		0.41		Gain of sheet (P = 0.1208)
MVP		0.18
MPC		0.093
ClinPred		0.87	D
GERP RS		2.9
Varity_R		0.12
gMVP		0.55
Mutation Taster		=83/17	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: rs200037793; hg19: chr8-67790820;