22-35400612-C-T

Variant names:

• chr22-35400612-C-T
• rs2307335
• NM_006739.4:c.167+7C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.153
• Publications: 2 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: Benign. The variant received -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 GnomAd4 at 6 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCM5	NM_006739.4	c.167+7C>T		splice_region_variant, intron_variant	Intron 2 of 16	ENST00000216122.9	NP_006730.2
MCM5	XM_006724242.5	c.167+7C>T		splice_region_variant, intron_variant	Intron 2 of 17		XP_006724305.1
MCM5	XM_047441366.1	c.167+7C>T		splice_region_variant, intron_variant	Intron 2 of 17		XP_047297322.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCM5	ENST00000216122.9	c.167+7C>T		splice_region_variant, intron_variant	Intron 2 of 16	1	NM_006739.4	ENSP00000216122.3

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

GnomAD2 exomes AF: 0.00625 AC: 1430 AN: 228724 AF XY: 0.00633

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 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

African (AFR) AF: 0.00163 AC: 54 AN: 33052

American (AMR) AF: 0.00332 AC: 144 AN: 43348

Ashkenazi Jewish (ASJ) AF: 0.00331 AC: 84 AN: 25356

East Asian (EAS) AF: 0.00 AC: 0 AN: 39336

South Asian (SAS) AF: 0.00166 AC: 141 AN: 84756

European-Finnish (FIN) AF: 0.00382 AC: 198 AN: 51786

Middle Eastern (MID) AF: 0.00189 AC: 10 AN: 5302

European-Non Finnish (NFE) AF: 0.0138 AC: 15247 AN: 1102440

Other (OTH) AF: 0.00999 AC: 595 AN: 59534

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

African (AFR) AF: 0.00246 AC: 102 AN: 41518

American (AMR) AF: 0.00523 AC: 80 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4806

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0116 AC: 789 AN: 68004

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MCM5: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.1
DANN	Benign	0.97
PhyloP100		0.15
PromoterAI		0.035	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2307335; hg19: chr22-35796605;