dbSNP rs2305023: MCPH1:c.-59G>C (chr8-6406609-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.357

Publications

14 publications found

Variant links:

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 links:

MCPH1-DT (HGNC:55599): (MCPH1 divergent transcript)

MCPH1-DT links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000519480.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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

Gene	Transcript	Tags	HGVSc	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.:

show subpopulations

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.:

AF XY:

0.751

AC XY:

536670

AN XY:

714296

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

13109

26218

39327

52436

65545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20348

40696

61044

81392

101740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.638

AC:

97040

AN:

152056

Hom.:

33640

Cov.:

AF XY:

0.635

AC XY:

47213

AN XY:

74322

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1579

3159

4738

6318

7897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.705

Hom.:

4944

Bravo

AF:

0.613

Asia WGS

AF:

0.568

AC:

1974

AN:

3476

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary Microcephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.3

(source)

DANN

Benign

0.59

PhyloP100

-0.36

PromoterAI

0.048

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over