8-6439029-G-A

Variant names:

• chr8-6439029-G-A
• rs2442513
• NM_024596.5:c.513G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_024596.5(MCPH1):​c.513G>A​(p.Arg171Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.351
• Publications: 38 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: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP7: Synonymous conserved (PhyloP=-0.351 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.513G>A	p.Arg171Arg	synonymous	Exon 6 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.513G>A	p.Arg171Arg	synonymous	Exon 6 of 15	NP_001308971.2
	MCPH1	NM_001410917.1		c.513G>A	p.Arg171Arg	synonymous	Exon 6 of 14	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.513G>A	p.Arg171Arg	synonymous	Exon 6 of 14	ENSP00000342924.5
	MCPH1	ENST00000519480.6	TSL:1	c.513G>A	p.Arg171Arg	synonymous	Exon 6 of 8	ENSP00000430962.1
	MCPH1	ENST00000692836.1		c.513G>A	p.Arg171Arg	synonymous	Exon 6 of 13	ENSP00000509971.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152046 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460778 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726820

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111270

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152046 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41312

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.42
DANN	Benign	0.53
PhyloP100		-0.35

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: rs2442513; hg19: chr8-6296550;