22-35400612-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006739.4(MCM5):c.167+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,597,058 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (120 hom.)
• Consequence: MCM5 NM_006739.4 splice_region, intron
• Scores: Splicing: ADA: 0.0006791
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.153

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 22-35400612-C-T is Benign according to our data. Variant chr22-35400612-C-T is described in ClinVar as [Benign]. Clinvar id is 770676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MCM5	NM_006739.4	c.167+7C>T		splice_region_variant, intron_variant		ENST00000216122.9
MCM5	XM_006724242.5	c.167+7C>T		splice_region_variant, intron_variant
MCM5	XM_047441366.1	c.167+7C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MCM5	ENST00000216122.9	c.167+7C>T		splice_region_variant, intron_variant		1	NM_006739.4	P1

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1050 AN: 152030 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00991

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00625 AC: 1430 AN: 228724 Hom.: 8 AF XY: 0.00633 AC XY: 794 AN XY: 125380

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00305

Gnomad ASJ exome AF: 0.00381

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00177

Gnomad FIN exome AF: 0.00369

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00664

GnomAD4 exome AF: 0.0114 AC: 16473 AN: 1444910 Hom.: 120 Cov.: 31 AF XY: 0.0110 AC XY: 7887 AN XY: 716900

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.00332

Gnomad4 ASJ exome AF: 0.00331

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00166

Gnomad4 FIN exome AF: 0.00382

Gnomad4 NFE exome AF: 0.0138

Gnomad4 OTH exome AF: 0.00999

GnomAD4 genome AF: 0.00689 AC: 1049 AN: 152148 Hom.: 6 Cov.: 32 AF XY: 0.00636 AC XY: 473 AN XY: 74382

Gnomad4 AFR AF: 0.00246

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00415

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00904 Hom.: 2

Bravo AF: 0.00664

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MCM5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.1
Dann	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00068
dbscSNV1_RF	Benign	0.0080
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

Publications

LitVar

Other links and lift over

dbSNP: rs2307335; hg19: chr22-35796605;