8-6621439-C-G

Variant names:

• chr8-6621439-C-G
• rs11137040
• NM_024596.5:c.2215-15C>G

Variant summary

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

The NM_001322042.2(MCPH1):​c.2215-15C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,606,776 control chromosomes in the GnomAD database, including 64,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5265 hom., cov: 33)
  • Exomes 𝑓: 0.28 (59324 hom.)
• Consequence: MCPH1 NM_001322042.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.593
• Publications: 9 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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-6621439-C-G is Benign according to our data. Variant chr8-6621439-C-G is described in ClinVar as Benign. ClinVar VariationId is 158842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322042.2. 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.2215-15C>G		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.2215-15C>G		intron	N/A	NP_001308971.2
	MCPH1	NM_001410917.1		c.2215-15C>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.2215-15C>G		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000692836.1		c.2215-15C>G		intron	N/A	ENSP00000509971.1
	MCPH1	ENST00000689348.1		c.2215-15C>G		intron	N/A	ENSP00000509554.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39445 AN: 151950 Hom.: 5258 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0742

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.259

GnomAD2 exomes AF: 0.243 AC: 60373 AN: 248108 AF XY: 0.250

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.0625

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.281 AC: 408159 AN: 1454708 Hom.: 59324 Cov.: 42 AF XY: 0.281 AC XY: 203163 AN XY: 723968

African (AFR) AF: 0.260 AC: 8693 AN: 33382

American (AMR) AF: 0.157 AC: 7013 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5788 AN: 26090

East Asian (EAS) AF: 0.119 AC: 4740 AN: 39700

South Asian (SAS) AF: 0.279 AC: 23998 AN: 86168

European-Finnish (FIN) AF: 0.273 AC: 14434 AN: 52950

Middle Eastern (MID) AF: 0.330 AC: 1900 AN: 5764

European-Non Finnish (NFE) AF: 0.295 AC: 325651 AN: 1105750

Other (OTH) AF: 0.265 AC: 15942 AN: 60196

GnomAD4 genome AF: 0.260 AC: 39482 AN: 152068 Hom.: 5265 Cov.: 33 AF XY: 0.256 AC XY: 19004 AN XY: 74304

African (AFR) AF: 0.259 AC: 10720 AN: 41466

American (AMR) AF: 0.187 AC: 2865 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 798 AN: 3472

East Asian (EAS) AF: 0.0742 AC: 384 AN: 5174

South Asian (SAS) AF: 0.254 AC: 1222 AN: 4820

European-Finnish (FIN) AF: 0.259 AC: 2737 AN: 10578

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19922 AN: 67952

Other (OTH) AF: 0.258 AC: 545 AN: 2114

Alfa AF: 0.194 Hom.: 583

Bravo AF: 0.253

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.4
DANN	Benign	0.64
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11137040; hg19: chr8-6478960;