rs2433148

Variant names:

• chr8-6642723-C-A
• rs2433148
• NM_024596.5:c.2453-271C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6642723-C-A
• chr8-6642723-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024596.5(MCPH1):​c.2453-271C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 507,330 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0410
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-6642723-C-A is Benign according to our data. Variant chr8-6642723-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1219303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0127 (1940/152158) while in subpopulation AFR AF = 0.0442 (1832/41494). AF 95% confidence interval is 0.0425. There are 43 homozygotes in GnomAd4. There are 924 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR gene

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.2453-271C>A		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.2595-271C>A		intron	N/A	NP_001308971.2
	MCPH1	NM_001363980.2		c.2174-271C>A		intron	N/A	NP_001350909.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2453-271C>A		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000521175.2	TSL:3	n.1219C>A		non_coding_transcript_exon	Exon 6 of 7
	MCPH1	ENST00000687324.1		n.1434C>A		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1933 AN: 152040 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00180 AC: 641 AN: 355172 Hom.: 9 Cov.: 0 AF XY: 0.00150 AC XY: 284 AN XY: 189376

African (AFR) AF: 0.0417 AC: 434 AN: 10416

American (AMR) AF: 0.00340 AC: 60 AN: 17652

Ashkenazi Jewish (ASJ) AF: 0.000368 AC: 4 AN: 10866

East Asian (EAS) AF: 0.00 AC: 0 AN: 21700

South Asian (SAS) AF: 0.0000450 AC: 2 AN: 44400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19008

Middle Eastern (MID) AF: 0.00204 AC: 3 AN: 1468

European-Non Finnish (NFE) AF: 0.000243 AC: 51 AN: 209588

Other (OTH) AF: 0.00433 AC: 87 AN: 20074

GnomAD4 genome AF: 0.0127 AC: 1940 AN: 152158 Hom.: 43 Cov.: 32 AF XY: 0.0124 AC XY: 924 AN XY: 74396

African (AFR) AF: 0.0442 AC: 1832 AN: 41494

American (AMR) AF: 0.00438 AC: 67 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67992

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00 Hom.: 1413

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.85
CADD	Benign	0.45
DANN	Benign	0.52
PhyloP100		-0.041
Mutation Taster		=100/0	polymorphism

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: rs2433148; hg19: chr8-6500244;