rs1031309

Variant names:

• chr8-6494837-A-C
• rs1031309
• NM_024596.5:c.2137-5015A>C

Your query was ambiguous. Multiple possible variants found:

• chr8-6494837-A-C
• chr8-6494837-A-G
• chr8-6494837-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.2137-5015A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 152,074 control chromosomes in the GnomAD database, including 35,282 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 0.65 (35282 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325
• Publications: 2 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.2137-5015A>C		intron_variant	Intron 11 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.2137-5015A>C		intron_variant	Intron 11 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98372 AN: 151956 Hom.: 35285 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.831

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.570

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.634

Gnomad NFE AF: 0.803

Gnomad OTH AF: 0.658

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

GnomAD4 genome AF: 0.647 AC: 98380 AN: 152074 Hom.: 35282 Cov.: 32 AF XY: 0.650 AC XY: 48299 AN XY: 74334

African (AFR) AF: 0.317 AC: 13159 AN: 41508

American (AMR) AF: 0.723 AC: 11052 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2445 AN: 3470

East Asian (EAS) AF: 0.571 AC: 2955 AN: 5176

South Asian (SAS) AF: 0.668 AC: 3210 AN: 4808

European-Finnish (FIN) AF: 0.824 AC: 8688 AN: 10548

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.803 AC: 54560 AN: 67974

Other (OTH) AF: 0.652 AC: 1375 AN: 2110

Alfa AF: 0.760 Hom.: 41725

Bravo AF: 0.628

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.75
DANN	Benign	0.62
PhyloP100		0.33
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: rs1031309; hg19: chr8-6352358;