8-6621465-C-T

Variant names:

• chr8-6621465-C-T
• rs2912010
• NM_024596.5:c.2226C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024596.5(MCPH1):​c.2226C>T​(p.Ser742Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,609,454 control chromosomes in the GnomAD database, including 139,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12661 hom., cov: 33)
  • Exomes 𝑓: 0.41 (126529 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.596
• Publications: 22 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-6621465-C-T is Benign according to our data. Variant chr8-6621465-C-T is described in ClinVar as Benign. ClinVar VariationId is 158844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.596 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 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.2226C>T	p.Ser742Ser	synonymous	Exon 13 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2226C>T	p.Ser742Ser	synonymous	Exon 13 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2226C>T	p.Ser742Ser	synonymous	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.2226C>T	p.Ser742Ser	synonymous	Exon 13 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2226C>T	p.Ser742Ser	synonymous	Exon 13 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2226C>T	p.Ser742Ser	synonymous	Exon 13 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61191 AN: 151902 Hom.: 12645 Cov.: 33

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.428 AC: 106400 AN: 248850 AF XY: 0.430

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.667

Gnomad FIN exome AF: 0.438

Gnomad NFE exome AF: 0.401

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.412 AC: 600865 AN: 1457434 Hom.: 126529 Cov.: 47 AF XY: 0.415 AC XY: 300822 AN XY: 725226

African (AFR) AF: 0.366 AC: 12228 AN: 33392

American (AMR) AF: 0.389 AC: 17376 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8644 AN: 26110

East Asian (EAS) AF: 0.681 AC: 27028 AN: 39692

South Asian (SAS) AF: 0.493 AC: 42482 AN: 86170

European-Finnish (FIN) AF: 0.445 AC: 23705 AN: 53234

Middle Eastern (MID) AF: 0.404 AC: 2329 AN: 5764

European-Non Finnish (NFE) AF: 0.399 AC: 442588 AN: 1108100

Other (OTH) AF: 0.406 AC: 24485 AN: 60254

GnomAD4 genome AF: 0.403 AC: 61245 AN: 152020 Hom.: 12661 Cov.: 33 AF XY: 0.408 AC XY: 30340 AN XY: 74296

African (AFR) AF: 0.363 AC: 15068 AN: 41472

American (AMR) AF: 0.380 AC: 5802 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1174 AN: 3466

East Asian (EAS) AF: 0.675 AC: 3488 AN: 5170

South Asian (SAS) AF: 0.492 AC: 2368 AN: 4814

European-Finnish (FIN) AF: 0.438 AC: 4622 AN: 10554

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27461 AN: 67950

Other (OTH) AF: 0.408 AC: 862 AN: 2114

Alfa AF: 0.396 Hom.: 17593

Bravo AF: 0.397

Asia WGS AF: 0.529 AC: 1843 AN: 3478

EpiCase AF: 0.395

EpiControl AF: 0.393

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.2
DANN	Benign	0.77
PhyloP100		-0.60
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: rs2912010; hg19: chr8-6478986; COSMIC: COSV60920674; COSMIC: COSV60920674;