rs930557

Variant names:

• chr8-6444662-G-C
• rs930557
• NM_024596.5:c.940G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-6444662-G-C
• chr8-6444662-G-T

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.940G>C​(p.Asp314His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 1,613,834 control chromosomes in the GnomAD database, including 511,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D314D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.68 (38517 hom., cov: 33)
  • Exomes 𝑓: 0.80 (473061 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.257
• Publications: 59 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=8.8958876E-7).
• BP6: Variant 8-6444662-G-C is Benign according to our data. Variant chr8-6444662-G-C is described in ClinVar as Benign. ClinVar VariationId is 21705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 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.940G>C	p.Asp314His	missense	Exon 8 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.940G>C	p.Asp314His	missense	Exon 8 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.940G>C	p.Asp314His	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.940G>C	p.Asp314His	missense	Exon 8 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.940G>C	p.Asp314His	missense	Exon 8 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.940G>C	p.Asp314His	missense	Exon 8 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103254 AN: 152040 Hom.: 38511 Cov.: 33

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.787

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.690

GnomAD2 exomes AF: 0.781 AC: 194302 AN: 248836 AF XY: 0.784

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.790

Gnomad FIN exome AF: 0.887

Gnomad NFE exome AF: 0.813

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.800 AC: 1169787 AN: 1461676 Hom.: 473061 Cov.: 62 AF XY: 0.800 AC XY: 581625 AN XY: 727120

African (AFR) AF: 0.321 AC: 10744 AN: 33474

American (AMR) AF: 0.849 AC: 37976 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 17988 AN: 26136

East Asian (EAS) AF: 0.793 AC: 31461 AN: 39698

South Asian (SAS) AF: 0.755 AC: 65122 AN: 86248

European-Finnish (FIN) AF: 0.884 AC: 47131 AN: 53296

Middle Eastern (MID) AF: 0.666 AC: 3839 AN: 5768

European-Non Finnish (NFE) AF: 0.818 AC: 909236 AN: 1111940

Other (OTH) AF: 0.766 AC: 46290 AN: 60394

GnomAD4 genome AF: 0.679 AC: 103273 AN: 152158 Hom.: 38517 Cov.: 33 AF XY: 0.687 AC XY: 51099 AN XY: 74414

African (AFR) AF: 0.336 AC: 13933 AN: 41458

American (AMR) AF: 0.790 AC: 12079 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2430 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4084 AN: 5186

South Asian (SAS) AF: 0.747 AC: 3601 AN: 4822

European-Finnish (FIN) AF: 0.880 AC: 9336 AN: 10606

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55392 AN: 68006

Other (OTH) AF: 0.692 AC: 1459 AN: 2108

Alfa AF: 0.785 Hom.: 35884

Bravo AF: 0.659

TwinsUK AF: 0.809 AC: 2998

ALSPAC AF: 0.811 AC: 3126

ESP6500AA AF: 0.374 AC: 1404

ESP6500EA AF: 0.814 AC: 6685

ExAC AF: 0.770 AC: 93070

Asia WGS AF: 0.745 AC: 2587 AN: 3478

EpiCase AF: 0.796

EpiControl AF: 0.798

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 (5)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	8.9e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.26
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.085
Sift	Benign	0.056	T
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.051
ClinPred		0.020	T
GERP RS		2.7
Varity_R		0.082
gMVP		0.22
Mutation Taster		=98/2	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: rs930557; hg19: chr8-6302183; COSMIC: COSV60915866;