rs35999761

Variant names:

• chr8-6621495-C-G
• rs35999761
• NM_024596.5:c.2256C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-6621495-C-G
• chr8-6621495-C-T
• chr8-6621495-C-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_024596.5(MCPH1):​c.2256C>G​(p.Arg752Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,614,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R752R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.346
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-6621495-C-G is Benign according to our data. Variant chr8-6621495-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158845.
• BP7: Synonymous conserved (PhyloP=-0.346 with no splicing effect.

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.2256C>G	p.Arg752Arg	synonymous	Exon 13 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2256C>G	p.Arg752Arg	synonymous	Exon 13 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2256C>G	p.Arg752Arg	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.2256C>G	p.Arg752Arg	synonymous	Exon 13 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2256C>G	p.Arg752Arg	synonymous	Exon 13 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2256C>G	p.Arg752Arg	synonymous	Exon 13 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249344 AF XY: 0.0000370

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 52 AN: 1461822 Hom.: 1 Cov.: 48 AF XY: 0.0000303 AC XY: 22 AN XY: 727220

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111998

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74484

African (AFR) AF: 0.000698 AC: 29 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000151 Hom.: 0

Bravo AF: 0.000208

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.58
PhyloP100		-0.35

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: rs35999761; hg19: chr8-6479016;