rs2922828

Variant names:

• chr8-6442120-G-A
• rs2922828
• NM_024596.5:c.634G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6442120-G-A
• chr8-6442120-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024596.5(MCPH1):​c.634G>A​(p.Ala212Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,298 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (56 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (45 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0180
• Publications: 5 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 Gene-Disease associations (from GenCC):

• microcephaly 1, primary, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microcephaly with intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016688406).
• BP6: Variant 8-6442120-G-A is Benign according to our data. Variant chr8-6442120-G-A is described in ClinVar as Benign. ClinVar VariationId is 158872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2257/152246) while in subpopulation AFR AF = 0.0509 (2115/41530). AF 95% confidence interval is 0.0491. There are 56 homozygotes in GnomAd4. There are 1074 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AD,AR gene

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.634G>A	p.Ala212Thr	missense	Exon 7 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.634G>A	p.Ala212Thr	missense	Exon 7 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.634G>A	p.Ala212Thr	missense	Exon 7 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.634G>A	p.Ala212Thr	missense	Exon 7 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.634G>A	p.Ala212Thr	missense	Exon 7 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.634G>A	p.Ala212Thr	missense	Exon 7 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2240 AN: 152128 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00363 AC: 905 AN: 249386 AF XY: 0.00281

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00157 AC: 2288 AN: 1461052 Hom.: 45 Cov.: 30 AF XY: 0.00136 AC XY: 989 AN XY: 726900

African (AFR) AF: 0.0503 AC: 1680 AN: 33420

American (AMR) AF: 0.00320 AC: 143 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86242

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53374

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.000172 AC: 191 AN: 1111372

Other (OTH) AF: 0.00409 AC: 247 AN: 60368

GnomAD4 genome AF: 0.0148 AC: 2257 AN: 152246 Hom.: 56 Cov.: 33 AF XY: 0.0144 AC XY: 1074 AN XY: 74434

African (AFR) AF: 0.0509 AC: 2115 AN: 41530

American (AMR) AF: 0.00595 AC: 91 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68016

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.00462 Hom.: 29

Bravo AF: 0.0161

ESP6500AA AF: 0.0467 AC: 172

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00470 AC: 568

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.039	N
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.018
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.052
Sift	Benign	0.24	T
Sift4G	Benign	0.53	T
Polyphen		0.31	B
Vest4		0.023
MVP		0.30
ClinPred		0.013	T
GERP RS		1.6
Varity_R		0.024
gMVP		0.18
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2922828; hg19: chr8-6299641;