8-6621639-C-T

Variant names:

• chr8-6621639-C-T
• rs7017210
• NM_024596.5:c.2400C>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.2400C>T​(p.Tyr800Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,614,226 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (164 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (126 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.67
• Publications: 2 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=-0.65).
• BP6: Variant 8-6621639-C-T is Benign according to our data. Variant chr8-6621639-C-T is described in ClinVar as Benign. ClinVar VariationId is 158855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0801 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.2400C>T	p.Tyr800Tyr	synonymous	Exon 13 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2400C>T	p.Tyr800Tyr	synonymous	Exon 13 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2400C>T	p.Tyr800Tyr	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.2400C>T	p.Tyr800Tyr	synonymous	Exon 13 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2400C>T	p.Tyr800Tyr	synonymous	Exon 13 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2400C>T	p.Tyr800Tyr	synonymous	Exon 13 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3591 AN: 152220 Hom.: 164 Cov.: 33

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00624 AC: 1557 AN: 249504 AF XY: 0.00448

Gnomad AFR exome AF: 0.0903

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00242 AC: 3539 AN: 1461888 Hom.: 126 Cov.: 51 AF XY: 0.00204 AC XY: 1482 AN XY: 727246

African (AFR) AF: 0.0858 AC: 2874 AN: 33480

American (AMR) AF: 0.00329 AC: 147 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.000103 AC: 115 AN: 1112008

Other (OTH) AF: 0.00520 AC: 314 AN: 60396

GnomAD4 genome AF: 0.0236 AC: 3595 AN: 152338 Hom.: 164 Cov.: 33 AF XY: 0.0232 AC XY: 1729 AN XY: 74500

African (AFR) AF: 0.0824 AC: 3425 AN: 41568

American (AMR) AF: 0.00732 AC: 112 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68040

Other (OTH) AF: 0.0132 AC: 28 AN: 2116

Alfa AF: 0.0137 Hom.: 63

Bravo AF: 0.0270

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	MCPH1-related disorder (1)
-	-	1	Microcephaly 1, primary, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.0
DANN	Benign	0.59
PhyloP100		1.7
Mutation Taster		=98/2	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: rs7017210; hg19: chr8-6479160;