rs2959804

Variant names:

• chr8-6611331-A-G
• rs2959804
• NM_024596.5:c.2215-10123A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-6611331-A-G
• chr8-6611331-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):​c.2215-10123A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.935 in 152,212 control chromosomes in the GnomAD database, including 66,900 homozygotes. 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 0.94 (66900 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.519
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2215-10123A>G		intron_variant	Intron 12 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2215-10123A>G		intron_variant	Intron 12 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.935 AC: 142257 AN: 152094 Hom.: 66866 Cov.: 32

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.926

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.908

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.934

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.935 AC: 142349 AN: 152212 Hom.: 66900 Cov.: 32 AF XY: 0.931 AC XY: 69264 AN XY: 74398

African (AFR) AF: 0.939 AC: 39006 AN: 41536

American (AMR) AF: 0.926 AC: 14167 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3221 AN: 3472

East Asian (EAS) AF: 0.619 AC: 3186 AN: 5144

South Asian (SAS) AF: 0.907 AC: 4372 AN: 4818

European-Finnish (FIN) AF: 0.908 AC: 9617 AN: 10594

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65608 AN: 68028

Other (OTH) AF: 0.935 AC: 1974 AN: 2112

Alfa AF: 0.930 Hom.: 19846

Bravo AF: 0.933

Asia WGS AF: 0.795 AC: 2764 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.37
PhyloP100		-0.52
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: rs2959804; hg19: chr8-6468852;