chr8-6621521-C-T

Variant names:

• chr8-6621521-C-T
• rs1057090
• NM_024596.5:c.2282C>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.2282C>T​(p.Ala761Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 1,613,234 control chromosomes in the GnomAD database, including 143,781 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A761G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.43 (14463 hom., cov: 33)
  • Exomes 𝑓: 0.42 (129318 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -0.503
• Publications: 46 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=3.4113652E-6).
• BP6: Variant 8-6621521-C-T is Benign according to our data. Variant chr8-6621521-C-T is described in ClinVar as Benign. ClinVar VariationId is 21702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.653 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.2282C>T	p.Ala761Val	missense	Exon 13 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2282C>T	p.Ala761Val	missense	Exon 13 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2282C>T	p.Ala761Val	missense	Exon 13 of 14	NP_001397846.1	A0A8I5KPV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2282C>T	p.Ala761Val	missense	Exon 13 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2282C>T	p.Ala761Val	missense	Exon 13 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2282C>T	p.Ala761Val	missense	Exon 13 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes AF: 0.432 AC: 65663 AN: 151916 Hom.: 14441 Cov.: 33

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.672

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.432

GnomAD2 exomes AF: 0.433 AC: 108048 AN: 249372 AF XY: 0.434

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.398

Gnomad ASJ exome AF: 0.339

Gnomad EAS exome AF: 0.662

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.401

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.417 AC: 609561 AN: 1461200 Hom.: 129318 Cov.: 52 AF XY: 0.419 AC XY: 304878 AN XY: 726940

African (AFR) AF: 0.477 AC: 15954 AN: 33464

American (AMR) AF: 0.397 AC: 17743 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 8781 AN: 26136

East Asian (EAS) AF: 0.676 AC: 26842 AN: 39700

South Asian (SAS) AF: 0.496 AC: 42757 AN: 86254

European-Finnish (FIN) AF: 0.417 AC: 22262 AN: 53376

Middle Eastern (MID) AF: 0.416 AC: 2398 AN: 5768

European-Non Finnish (NFE) AF: 0.403 AC: 447739 AN: 1111418

Other (OTH) AF: 0.416 AC: 25085 AN: 60368

GnomAD4 genome AF: 0.432 AC: 65728 AN: 152034 Hom.: 14463 Cov.: 33 AF XY: 0.436 AC XY: 32366 AN XY: 74304

African (AFR) AF: 0.470 AC: 19492 AN: 41484

American (AMR) AF: 0.393 AC: 5998 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1189 AN: 3470

East Asian (EAS) AF: 0.672 AC: 3468 AN: 5162

South Asian (SAS) AF: 0.494 AC: 2381 AN: 4824

European-Finnish (FIN) AF: 0.408 AC: 4311 AN: 10558

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27574 AN: 67944

Other (OTH) AF: 0.431 AC: 910 AN: 2110

Alfa AF: 0.415 Hom.: 62238

Bravo AF: 0.433

TwinsUK AF: 0.382 AC: 1416

ALSPAC AF: 0.394 AC: 1517

ESP6500AA AF: 0.444 AC: 1888

ESP6500EA AF: 0.392 AC: 3316

ExAC AF: 0.436 AC: 52750

Asia WGS AF: 0.530 AC: 1846 AN: 3478

EpiCase AF: 0.399

EpiControl AF: 0.395

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.18
DANN	Benign	0.70
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0056	N
MetaRNN	Benign	0.0000034	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.50
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.011
ClinPred		0.0058	T
GERP RS		-8.3
Varity_R		0.031
gMVP		0.26
Mutation Taster		=97/3	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: rs1057090; hg19: chr8-6479042; COSMIC: COSV60910792; COSMIC: COSV60910792;