NM_024596.5:c.2136+267T>G

Variant names:

• chr8-6481143-T-G
• rs12677501
• NM_024596.5:c.2136+267T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024596.5(MCPH1):​c.2136+267T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,152 control chromosomes in the GnomAD database, including 1,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.16 (1994 hom., cov: 32)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-6481143-T-G is Benign according to our data. Variant chr8-6481143-T-G is described in ClinVar as Benign. ClinVar VariationId is 1265419.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2136+267T>G		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.2136+267T>G		intron	N/A	NP_001308971.2
	MCPH1	NM_001410917.1		c.2136+267T>G		intron	N/A	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2136+267T>G		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.2136+267T>G		intron	N/A	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.2136+267T>G		intron	N/A	ENSP00000509554.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23783 AN: 152034 Hom.: 1994 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0963

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.156 AC: 23789 AN: 152152 Hom.: 1994 Cov.: 32 AF XY: 0.153 AC XY: 11417 AN XY: 74388

African (AFR) AF: 0.140 AC: 5809 AN: 41500

American (AMR) AF: 0.136 AC: 2073 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3464

East Asian (EAS) AF: 0.201 AC: 1039 AN: 5162

South Asian (SAS) AF: 0.198 AC: 956 AN: 4822

European-Finnish (FIN) AF: 0.0963 AC: 1021 AN: 10598

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11501 AN: 68002

Other (OTH) AF: 0.178 AC: 376 AN: 2116

Alfa AF: 0.161 Hom.: 340

Bravo AF: 0.156

Asia WGS AF: 0.186 AC: 647 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.12
DANN	Benign	0.60
PhyloP100		-1.3
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: rs12677501; hg19: chr8-6338664;