chr8-6406609-G-C

Variant names:

• chr8-6406609-G-C
• rs2305023
• ENST00000519480.6:c.-59G>C

Variant summary

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

The ENST00000519480.6(MCPH1):​c.-59G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,590,766 control chromosomes in the GnomAD database, including 448,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (33640 hom., cov: 34)
  • Exomes 𝑓: 0.75 (414660 hom.)
• Consequence: MCPH1 ENST00000519480.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.357
• Publications: 14 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-DT (HGNC:55599): (MCPH1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-6406609-G-C is Benign according to our data. Variant chr8-6406609-G-C is described in ClinVar as Benign. ClinVar VariationId is 363515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000519480.6. 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.-59G>C		upstream_gene	N/A	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.-59G>C		upstream_gene	N/A	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.-59G>C		upstream_gene	N/A	NP_001397846.1	A0A8I5KPV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000519480.6	TSL:1	c.-59G>C		5_prime_UTR	Exon 1 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692938.1		c.-59G>C		5_prime_UTR	Exon 1 of 14	ENSP00000509072.1	A0A8I5KPV6
	MCPH1	ENST00000690826.1		c.-59G>C		5_prime_UTR	Exon 1 of 14	ENSP00000510536.1	A0A8I5KW78

Frequencies

GnomAD3 genomes AF: 0.638 AC: 97008 AN: 151938 Hom.: 33638 Cov.: 34

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.792

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.753 AC: 1083070 AN: 1438710 Hom.: 414660 Cov.: 31 AF XY: 0.751 AC XY: 536670 AN XY: 714296

African (AFR) AF: 0.367 AC: 11972 AN: 32618

American (AMR) AF: 0.543 AC: 22764 AN: 41894

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 17579 AN: 25486

East Asian (EAS) AF: 0.489 AC: 18956 AN: 38786

South Asian (SAS) AF: 0.625 AC: 52394 AN: 83788

European-Finnish (FIN) AF: 0.810 AC: 40770 AN: 50326

Middle Eastern (MID) AF: 0.656 AC: 3515 AN: 5358

European-Non Finnish (NFE) AF: 0.792 AC: 872393 AN: 1101068

Other (OTH) AF: 0.719 AC: 42727 AN: 59386

GnomAD4 genome AF: 0.638 AC: 97040 AN: 152056 Hom.: 33640 Cov.: 34 AF XY: 0.635 AC XY: 47213 AN XY: 74322

African (AFR) AF: 0.375 AC: 15571 AN: 41500

American (AMR) AF: 0.589 AC: 8996 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2390 AN: 3472

East Asian (EAS) AF: 0.478 AC: 2445 AN: 5110

South Asian (SAS) AF: 0.622 AC: 3000 AN: 4824

European-Finnish (FIN) AF: 0.792 AC: 8406 AN: 10614

Middle Eastern (MID) AF: 0.651 AC: 190 AN: 292

European-Non Finnish (NFE) AF: 0.792 AC: 53824 AN: 67938

Other (OTH) AF: 0.645 AC: 1362 AN: 2112

Alfa AF: 0.705 Hom.: 4944

Bravo AF: 0.613

Asia WGS AF: 0.568 AC: 1974 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.3
DANN	Benign	0.59
PhyloP100		-0.36
PromoterAI		0.048	Neutral
Mutation Taster		=300/0	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: rs2305023; hg19: chr8-6264130; COSMIC: COSV60911521; COSMIC: COSV60911521;