rs2920676

Variant names:

• chr8-6445150-C-T
• rs2920676
• NM_024596.5:c.1428C>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.1428C>T​(p.Phe476Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,614,124 control chromosomes in the GnomAD database, including 8,961 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3760 hom., cov: 33)
  • Exomes 𝑓: 0.042 (5201 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.895
• Publications: 11 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=-0.85).
• BP6: Variant 8-6445150-C-T is Benign according to our data. Variant chr8-6445150-C-T is described in ClinVar as Benign. ClinVar VariationId is 96128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.895 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 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.1428C>T	p.Phe476Phe	synonymous	Exon 8 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.1428C>T	p.Phe476Phe	synonymous	Exon 8 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.1428C>T	p.Phe476Phe	synonymous	Exon 8 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.1428C>T	p.Phe476Phe	synonymous	Exon 8 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.1428C>T	p.Phe476Phe	synonymous	Exon 8 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.1428C>T	p.Phe476Phe	synonymous	Exon 8 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21858 AN: 152124 Hom.: 3747 Cov.: 33

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.0377

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.0795 AC: 19828 AN: 249454 AF XY: 0.0761

Gnomad AFR exome AF: 0.430

Gnomad AMR exome AF: 0.0610

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0423 AC: 61889 AN: 1461882 Hom.: 5201 Cov.: 53 AF XY: 0.0440 AC XY: 32006 AN XY: 727246

African (AFR) AF: 0.424 AC: 14190 AN: 33478

American (AMR) AF: 0.0618 AC: 2764 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 948 AN: 26136

East Asian (EAS) AF: 0.155 AC: 6160 AN: 39700

South Asian (SAS) AF: 0.149 AC: 12849 AN: 86258

European-Finnish (FIN) AF: 0.0353 AC: 1888 AN: 53414

Middle Eastern (MID) AF: 0.0756 AC: 436 AN: 5768

European-Non Finnish (NFE) AF: 0.0168 AC: 18633 AN: 1112010

Other (OTH) AF: 0.0666 AC: 4021 AN: 60394

GnomAD4 genome AF: 0.144 AC: 21911 AN: 152242 Hom.: 3760 Cov.: 33 AF XY: 0.143 AC XY: 10633 AN XY: 74442

African (AFR) AF: 0.409 AC: 16975 AN: 41492

American (AMR) AF: 0.0812 AC: 1242 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0377 AC: 131 AN: 3472

East Asian (EAS) AF: 0.161 AC: 831 AN: 5174

South Asian (SAS) AF: 0.157 AC: 757 AN: 4830

European-Finnish (FIN) AF: 0.0392 AC: 416 AN: 10614

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1261 AN: 68038

Other (OTH) AF: 0.130 AC: 274 AN: 2114

Alfa AF: 0.0661 Hom.: 2209

Bravo AF: 0.158

Asia WGS AF: 0.166 AC: 578 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.63
DANN	Benign	0.40
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

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: rs2920676; hg19: chr8-6302671; COSMIC: COSV60920903;