rs2912016

Variant names:

• chr8-6621657-C-A
• rs2912016
• NM_024596.5:c.2418C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6621657-C-A
• chr8-6621657-C-G
• chr8-6621657-C-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.2418C>A​(p.Ala806Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,613,730 control chromosomes in the GnomAD database, including 106,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A806A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (10740 hom., cov: 33)
  • Exomes 𝑓: 0.36 (95947 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.28
• Publications: 27 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=-0.83).
• BP6: Variant 8-6621657-C-A is Benign according to our data. Variant chr8-6621657-C-A is described in ClinVar as Benign. ClinVar VariationId is 158857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 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.2418C>A	p.Ala806Ala	synonymous	Exon 13 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2418C>A	p.Ala806Ala	synonymous	Exon 13 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2418C>A	p.Ala806Ala	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.2418C>A	p.Ala806Ala	synonymous	Exon 13 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2418C>A	p.Ala806Ala	synonymous	Exon 13 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2418C>A	p.Ala806Ala	synonymous	Exon 13 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56918 AN: 151976 Hom.: 10722 Cov.: 33

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.364 AC: 90860 AN: 249360 AF XY: 0.367

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.303

Gnomad EAS exome AF: 0.426

Gnomad FIN exome AF: 0.366

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.361 AC: 527805 AN: 1461636 Hom.: 95947 Cov.: 43 AF XY: 0.363 AC XY: 263955 AN XY: 727124

African (AFR) AF: 0.428 AC: 14328 AN: 33476

American (AMR) AF: 0.319 AC: 14272 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 7866 AN: 26134

East Asian (EAS) AF: 0.447 AC: 17753 AN: 39694

South Asian (SAS) AF: 0.427 AC: 36860 AN: 86250

European-Finnish (FIN) AF: 0.372 AC: 19880 AN: 53414

Middle Eastern (MID) AF: 0.400 AC: 2309 AN: 5768

European-Non Finnish (NFE) AF: 0.353 AC: 392830 AN: 1111790

Other (OTH) AF: 0.359 AC: 21707 AN: 60390

GnomAD4 genome AF: 0.375 AC: 56973 AN: 152094 Hom.: 10740 Cov.: 33 AF XY: 0.377 AC XY: 28055 AN XY: 74328

African (AFR) AF: 0.421 AC: 17472 AN: 41506

American (AMR) AF: 0.336 AC: 5137 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3472

East Asian (EAS) AF: 0.430 AC: 2218 AN: 5158

South Asian (SAS) AF: 0.415 AC: 2001 AN: 4822

European-Finnish (FIN) AF: 0.368 AC: 3885 AN: 10562

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24069 AN: 67986

Other (OTH) AF: 0.369 AC: 778 AN: 2110

Alfa AF: 0.352 Hom.: 15268

Bravo AF: 0.373

Asia WGS AF: 0.387 AC: 1344 AN: 3478

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	-0.83
CADD	Benign	0.034
DANN	Benign	0.64
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs2912016; hg19: chr8-6479178; COSMIC: COSV60911550; COSMIC: COSV60911550;