NM_024596.5:c.1175A>G

Variant names:

• chr8-6444897-A-G
• rs2515569
• NM_024596.5:c.1175A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024596.5(MCPH1):​c.1175A>G​(p.Asp392Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,614,206 control chromosomes in the GnomAD database, including 804,919 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.99 (75016 hom., cov: 32)
  • Exomes 𝑓: 1.0 (729903 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.71
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0807453E-6).
• BP6: Variant 8-6444897-A-G is Benign according to our data. Variant chr8-6444897-A-G is described in ClinVar as Benign. ClinVar VariationId is 96126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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.1175A>G	p.Asp392Gly	missense	Exon 8 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.1175A>G	p.Asp392Gly	missense	Exon 8 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.1175A>G	p.Asp392Gly	missense	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.1175A>G	p.Asp392Gly	missense	Exon 8 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.1175A>G	p.Asp392Gly	missense	Exon 8 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.1175A>G	p.Asp392Gly	missense	Exon 8 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.992 AC: 151041 AN: 152196 Hom.: 74959 Cov.: 32

Gnomad AFR AF: 0.973

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.998 AC: 248903 AN: 249358 AF XY: 0.999

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 0.999 AC: 1460831 AN: 1461892 Hom.: 729903 Cov.: 78 AF XY: 0.999 AC XY: 726805 AN XY: 727246

African (AFR) AF: 0.973 AC: 32586 AN: 33480

American (AMR) AF: 0.999 AC: 44678 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26136 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39695 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86252 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53418 AN: 53418

Middle Eastern (MID) AF: 0.999 AC: 5761 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1112000 AN: 1112012

Other (OTH) AF: 0.998 AC: 60305 AN: 60396

GnomAD4 genome AF: 0.992 AC: 151157 AN: 152314 Hom.: 75016 Cov.: 32 AF XY: 0.993 AC XY: 73921 AN XY: 74474

African (AFR) AF: 0.973 AC: 40444 AN: 41556

American (AMR) AF: 0.998 AC: 15279 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68032 AN: 68034

Other (OTH) AF: 0.994 AC: 2101 AN: 2114

Alfa AF: 0.997 Hom.: 190960

Bravo AF: 0.991

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.978 AC: 3938

ESP6500EA AF: 1.00 AC: 8371

ExAC AF: 0.998 AC: 120602

Asia WGS AF: 0.999 AC: 3475 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Microcephaly 1, primary, autosomal recessive (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0040
DANN	Benign	0.32
DEOGEN2	Benign	0.077	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0036	N
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-3.7
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.044
Sift	Benign	0.57	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.031
ClinPred		0.024	T
GERP RS		-12
Varity_R		0.032
gMVP		0.14
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: rs2515569; hg19: chr8-6302418; COSMIC: COSV107433839;