8-6643007-G-A

Variant names:

• chr8-6643007-G-A
• rs35614690
• NM_024596.5:c.2466G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001322042.2(MCPH1):​c.2608G>A​(p.Ala870Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,613,932 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (9 hom.)
• Consequence: MCPH1 NM_001322042.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.586
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 8-6643007-G-A is Benign according to our data. Variant chr8-6643007-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158864.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00235 (3431/1461638) while in subpopulation NFE AF = 0.00283 (3147/1111814). AF 95% confidence interval is 0.00275. There are 9 homozygotes in GnomAdExome4. There are 1662 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322042.2. 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.2466G>A	p.Gln822Gln	synonymous	Exon 14 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.2608G>A	p.Ala870Thr	missense	Exon 15 of 15	NP_001308971.2
	MCPH1	NM_001363980.2		c.2187G>A	p.Gln729Gln	synonymous	Exon 11 of 11	NP_001350909.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2466G>A	p.Gln822Gln	synonymous	Exon 14 of 14	ENSP00000342924.5
	MCPH1	ENST00000689348.1		c.2608G>A	p.Ala870Thr	missense	Exon 15 of 15	ENSP00000509554.1
	MCPH1	ENST00000949609.1		c.2388G>A	p.Gln796Gln	synonymous	Exon 13 of 13	ENSP00000619668.1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 249 AN: 152176 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00126 AC: 315 AN: 249404 AF XY: 0.00112

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00235 AC: 3431 AN: 1461638 Hom.: 9 Cov.: 29 AF XY: 0.00229 AC XY: 1662 AN XY: 727126

African (AFR) AF: 0.000418 AC: 14 AN: 33476

American (AMR) AF: 0.000783 AC: 35 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00251 AC: 134 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00283 AC: 3147 AN: 1111814

Other (OTH) AF: 0.00162 AC: 98 AN: 60392

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152294 Hom.: 4 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74460

African (AFR) AF: 0.000673 AC: 28 AN: 41574

American (AMR) AF: 0.000654 AC: 10 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00279 AC: 190 AN: 68034

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00135

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Microcephaly 1, primary, autosomal recessive (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.6
DANN	Benign	0.78
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism

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: rs35614690; hg19: chr8-6500528;