NM_024596.5:c.228G>T

Variant names:

• chr8-6414878-G-T
• rs2305022
• NM_024596.5:c.228G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024596.5(MCPH1):​c.228G>T​(p.Val76Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,612,258 control chromosomes in the GnomAD database, including 498,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (39458 hom., cov: 29)
  • Exomes 𝑓: 0.79 (459509 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.21
• Publications: 26 publications found

Genes affected

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

MCPH1 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-6414878-G-T is Benign according to our data. Variant chr8-6414878-G-T is described in ClinVar as Benign. ClinVar VariationId is 158851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. 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
	MCPH1	NM_024596.5	MANE Select	c.228G>T	p.Val76Val	synonymous	Exon 3 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.228G>T	p.Val76Val	synonymous	Exon 3 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.228G>T	p.Val76Val	synonymous	Exon 3 of 14	NP_001397846.1	A0A8I5KPV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.228G>T	p.Val76Val	synonymous	Exon 3 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.228G>T	p.Val76Val	synonymous	Exon 3 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.228G>T	p.Val76Val	synonymous	Exon 3 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106222 AN: 151218 Hom.: 39439 Cov.: 29

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.802

Gnomad OTH AF: 0.708

GnomAD2 exomes AF: 0.779 AC: 194367 AN: 249410 AF XY: 0.780

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.691

Gnomad EAS exome AF: 0.787

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.786

GnomAD4 exome AF: 0.790 AC: 1154498 AN: 1460924 Hom.: 459509 Cov.: 42 AF XY: 0.790 AC XY: 573782 AN XY: 726748

African (AFR) AF: 0.427 AC: 14287 AN: 33460

American (AMR) AF: 0.851 AC: 38027 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 17965 AN: 26108

East Asian (EAS) AF: 0.785 AC: 31120 AN: 39656

South Asian (SAS) AF: 0.743 AC: 64020 AN: 86202

European-Finnish (FIN) AF: 0.890 AC: 47513 AN: 53366

Middle Eastern (MID) AF: 0.655 AC: 3771 AN: 5758

European-Non Finnish (NFE) AF: 0.802 AC: 891728 AN: 1111304

Other (OTH) AF: 0.763 AC: 46067 AN: 60360

GnomAD4 genome AF: 0.702 AC: 106273 AN: 151334 Hom.: 39458 Cov.: 29 AF XY: 0.709 AC XY: 52402 AN XY: 73858

African (AFR) AF: 0.438 AC: 18010 AN: 41118

American (AMR) AF: 0.796 AC: 12055 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2424 AN: 3468

East Asian (EAS) AF: 0.786 AC: 4058 AN: 5166

South Asian (SAS) AF: 0.733 AC: 3491 AN: 4760

European-Finnish (FIN) AF: 0.891 AC: 9324 AN: 10468

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.802 AC: 54466 AN: 67920

Other (OTH) AF: 0.710 AC: 1479 AN: 2084

Alfa AF: 0.754 Hom.: 67224

Bravo AF: 0.686

Asia WGS AF: 0.747 AC: 2595 AN: 3478

EpiCase AF: 0.784

EpiControl AF: 0.784

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Microcephaly 1, primary, autosomal recessive (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.44
DANN	Benign	0.56
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2305022; hg19: chr8-6272399; COSMIC: COSV108162629;