chr22-35400517-C-A

Variant names:

• chr22-35400517-C-A
• rs1213676370
• NM_006739.4:c.79C>A

Variant summary

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

The NM_006739.4(MCM5):​c.79C>A​(p.Arg27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. R27G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MCM5 NM_006739.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• Publications: 0 publications found

Genes affected

MCM5 (HGNC:6948): (minichromosome maintenance complex component 5) The protein encoded by this gene is structurally very similar to the CDC46 protein from S. cerevisiae, a protein involved in the initiation of DNA replication. The encoded protein is a member of the MCM family of chromatin-binding proteins and can interact with at least two other members of this family. The encoded protein is upregulated in the transition from the G0 to G1/S phase of the cell cycle and may actively participate in cell cycle regulation. [provided by RefSeq, Jul 2008]

MCM5 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 8

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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=0.10599336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM5	NM_006739.4	c.79C>A	p.Arg27Ser	missense_variant	Exon 2 of 17	ENST00000216122.9	NP_006730.2
MCM5	XM_006724242.5	c.79C>A	p.Arg27Ser	missense_variant	Exon 2 of 18		XP_006724305.1
MCM5	XM_047441366.1	c.79C>A	p.Arg27Ser	missense_variant	Exon 2 of 18		XP_047297322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM5	ENST00000216122.9	c.79C>A	p.Arg27Ser	missense_variant	Exon 2 of 17	1	NM_006739.4	ENSP00000216122.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.
PhyloP100		2.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.61	N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.82	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.74
MutPred		0.28		Loss of MoRF binding (P = 0.0465);Loss of MoRF binding (P = 0.0465);Loss of MoRF binding (P = 0.0465);
MVP		0.50
MPC		0.41
ClinPred		0.66	D
GERP RS		4.1
PromoterAI		-0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.47
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1213676370; hg19: chr22-35796510; COSMIC: COSV99332053;