rs1057091

Variant names:

• chr8-6643023-C-T
• rs1057091
• NM_024596.5:c.2482C>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.2482C>T​(p.Pro828Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,612,652 control chromosomes in the GnomAD database, including 75,303 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P828P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (5685 hom., cov: 32)
  • Exomes 𝑓: 0.31 (69618 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.293
• Publications: 43 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 (MetaRNN=0.002649963).
• BP6: Variant 8-6643023-C-T is Benign according to our data. Variant chr8-6643023-C-T is described in ClinVar as Benign. ClinVar VariationId is 21703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.374 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.2482C>T	p.Pro828Ser	missense	Exon 14 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2624C>T	p.Pro875Leu	missense	Exon 15 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001363980.2		c.2203C>T	p.Pro735Ser	missense	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.2482C>T	p.Pro828Ser	missense	Exon 14 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000689348.1		c.2624C>T	p.Pro875Leu	missense	Exon 15 of 15	ENSP00000509554.1	A0A8I5KV10
	MCPH1	ENST00000949609.1		c.2404C>T	p.Pro802Ser	missense	Exon 13 of 13	ENSP00000619668.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40440 AN: 151942 Hom.: 5678 Cov.: 32

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.285 AC: 71022 AN: 249044 AF XY: 0.295

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.306 AC: 447083 AN: 1460592 Hom.: 69618 Cov.: 34 AF XY: 0.310 AC XY: 224911 AN XY: 726664

African (AFR) AF: 0.191 AC: 6379 AN: 33440

American (AMR) AF: 0.195 AC: 8696 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 8043 AN: 26126

East Asian (EAS) AF: 0.272 AC: 10782 AN: 39692

South Asian (SAS) AF: 0.393 AC: 33822 AN: 86166

European-Finnish (FIN) AF: 0.293 AC: 15619 AN: 53372

Middle Eastern (MID) AF: 0.343 AC: 1976 AN: 5764

European-Non Finnish (NFE) AF: 0.310 AC: 343876 AN: 1110978

Other (OTH) AF: 0.296 AC: 17890 AN: 60350

GnomAD4 genome AF: 0.266 AC: 40477 AN: 152060 Hom.: 5685 Cov.: 32 AF XY: 0.268 AC XY: 19896 AN XY: 74312

African (AFR) AF: 0.193 AC: 7994 AN: 41474

American (AMR) AF: 0.205 AC: 3135 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1100 AN: 3464

East Asian (EAS) AF: 0.222 AC: 1145 AN: 5166

South Asian (SAS) AF: 0.389 AC: 1875 AN: 4822

European-Finnish (FIN) AF: 0.280 AC: 2956 AN: 10540

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21328 AN: 67998

Other (OTH) AF: 0.277 AC: 585 AN: 2114

Alfa AF: 0.301 Hom.: 32069

Bravo AF: 0.255

TwinsUK AF: 0.288 AC: 1067

ALSPAC AF: 0.308 AC: 1188

ESP6500AA AF: 0.186 AC: 730

ESP6500EA AF: 0.302 AC: 2508

ExAC AF: 0.292 AC: 35252

Asia WGS AF: 0.292 AC: 1016 AN: 3478

EpiCase AF: 0.310

EpiControl AF: 0.311

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Microcephaly 1, primary, autosomal recessive (6)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.5
DANN	Benign	0.74
DEOGEN2	Benign	0.055	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00036	N
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N
PhyloP100		0.29
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.17
Sift	Benign	0.41	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.017
ClinPred		0.00018	T
GERP RS		-1.4
Varity_R		0.096
gMVP		0.28
Mutation Taster		=97/3	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: rs1057091; hg19: chr8-6500544; COSMIC: COSV60913742;