rs2433149

Variant names:

• chr8-6643230-C-G
• rs2433149
• NM_024596.5:c.*181C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-6643230-C-G
• chr8-6643230-C-T

Variant summary

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

The NM_024596.5(MCPH1):​c.*181C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 664,116 control chromosomes in the GnomAD database, including 33,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7189 hom., cov: 33)
  • Exomes 𝑓: 0.31 (26069 hom.)
• Consequence: MCPH1 NM_024596.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.165
• 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=-0.95).
• BP6: Variant 8-6643230-C-G is Benign according to our data. Variant chr8-6643230-C-G is described in ClinVar as Benign. ClinVar VariationId is 363567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.375 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.*181C>G		3_prime_UTR	Exon 14 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.*203C>G		3_prime_UTR	Exon 15 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001363980.2		c.*181C>G		3_prime_UTR	Exon 11 of 11	NP_001350909.1	A0A8I5KR97

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.*181C>G		3_prime_UTR	Exon 14 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000949609.1		c.*181C>G		3_prime_UTR	Exon 13 of 13	ENSP00000619668.1
	MCPH1	ENST00000933168.1		c.*181C>G		3_prime_UTR	Exon 12 of 12	ENSP00000603227.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46364 AN: 152078 Hom.: 7173 Cov.: 33

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.315 AC: 161002 AN: 511920 Hom.: 26069 Cov.: 4 AF XY: 0.319 AC XY: 87641 AN XY: 274782

African (AFR) AF: 0.328 AC: 4583 AN: 13982

American (AMR) AF: 0.209 AC: 5646 AN: 27020

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 5472 AN: 17758

East Asian (EAS) AF: 0.286 AC: 9024 AN: 31558

South Asian (SAS) AF: 0.393 AC: 21863 AN: 55630

European-Finnish (FIN) AF: 0.294 AC: 9924 AN: 33804

Middle Eastern (MID) AF: 0.331 AC: 960 AN: 2896

European-Non Finnish (NFE) AF: 0.315 AC: 94842 AN: 300708

Other (OTH) AF: 0.304 AC: 8688 AN: 28564

GnomAD4 genome AF: 0.305 AC: 46420 AN: 152196 Hom.: 7189 Cov.: 33 AF XY: 0.305 AC XY: 22711 AN XY: 74392

African (AFR) AF: 0.323 AC: 13402 AN: 41546

American (AMR) AF: 0.223 AC: 3415 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1100 AN: 3468

East Asian (EAS) AF: 0.222 AC: 1149 AN: 5174

South Asian (SAS) AF: 0.390 AC: 1880 AN: 4824

European-Finnish (FIN) AF: 0.280 AC: 2968 AN: 10588

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.316 AC: 21498 AN: 67984

Other (OTH) AF: 0.306 AC: 645 AN: 2110

Alfa AF: 0.304 Hom.: 931

Bravo AF: 0.298

Asia WGS AF: 0.301 AC: 1049 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.7
DANN	Benign	0.71
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2433149; hg19: chr8-6500751; COSMIC: COSV60920476;