8-66896903-C-T

Variant names:

• chr8-66896903-C-T
• rs35871529
• NM_173518.5:c.1570C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173518.5(MCMDC2):​c.1570C>T​(p.Pro524Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00297 in 1,612,794 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (65 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (64 hom.)
• Consequence: MCMDC2 NM_173518.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.52
• Publications: 5 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]

SNHG6 (HGNC:32965): (small nucleolar RNA host gene 6)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034536123).
• BP6: Variant 8-66896903-C-T is Benign according to our data. Variant chr8-66896903-C-T is described in ClinVar as Benign. ClinVar VariationId is 783526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

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.1570C>T	p.Pro524Ser	missense	Exon 12 of 15	NP_775789.3
	MCMDC2	NM_001136160.2		c.1570C>T	p.Pro524Ser	missense	Exon 12 of 14	NP_001129632.1	B4DXX4
	MCMDC2	NM_001136161.2		c.1570C>T	p.Pro524Ser	missense	Exon 12 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.1570C>T	p.Pro524Ser	missense	Exon 12 of 15	ENSP00000413632.2	Q4G0Z9-1
	MCMDC2	ENST00000396592.7	TSL:1	c.1570C>T	p.Pro524Ser	missense	Exon 12 of 13	ENSP00000379837.3	Q4G0Z9-2
	MCMDC2	ENST00000872356.1		c.1516C>T	p.Pro506Ser	missense	Exon 12 of 15	ENSP00000542415.1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2475 AN: 152116 Hom.: 65 Cov.: 32

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00415 AC: 1037 AN: 249770 AF XY: 0.00293

Gnomad AFR exome AF: 0.0564

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00158 AC: 2312 AN: 1460562 Hom.: 64 Cov.: 30 AF XY: 0.00135 AC XY: 979 AN XY: 726550

African (AFR) AF: 0.0543 AC: 1814 AN: 33380

American (AMR) AF: 0.00348 AC: 155 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.000105 AC: 9 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.0000666 AC: 74 AN: 1111470

Other (OTH) AF: 0.00414 AC: 250 AN: 60350

GnomAD4 genome AF: 0.0162 AC: 2473 AN: 152232 Hom.: 65 Cov.: 32 AF XY: 0.0155 AC XY: 1155 AN XY: 74432

African (AFR) AF: 0.0551 AC: 2286 AN: 41512

American (AMR) AF: 0.00902 AC: 138 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68024

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00605 Hom.: 65

Bravo AF: 0.0188

ESP6500AA AF: 0.0563 AC: 248

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00516 AC: 626

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0027	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.22
MVP		0.35
MPC		0.083
ClinPred		0.035	T
GERP RS		5.5
Varity_R		0.091
gMVP		0.38
Mutation Taster		=95/5	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: rs35871529; hg19: chr8-67809138; COSMIC: COSV58033259;