rs12674488

Variant names:

• chr8-6480785-C-A
• rs12674488
• NM_024596.5:c.2045C>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6480785-C-A
• chr8-6480785-C-G
• chr8-6480785-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024596.5(MCPH1):​c.2045C>A​(p.Thr682Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,986 control chromosomes in the GnomAD database, including 19,359 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T682T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1574 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17785 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.11
• Publications: 32 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=9.829998E-4).
• BP6: Variant 8-6480785-C-A is Benign according to our data. Variant chr8-6480785-C-A is described in ClinVar as Benign. ClinVar VariationId is 158834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 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.2045C>A	p.Thr682Asn	missense	Exon 11 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2045C>A	p.Thr682Asn	missense	Exon 11 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2045C>A	p.Thr682Asn	missense	Exon 11 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.2045C>A	p.Thr682Asn	missense	Exon 11 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2045C>A	p.Thr682Asn	missense	Exon 11 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2045C>A	p.Thr682Asn	missense	Exon 11 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20642 AN: 152058 Hom.: 1575 Cov.: 32

Gnomad AFR AF: 0.0945

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0925

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.149 AC: 37271 AN: 249570 AF XY: 0.153

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.253

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.0853

Gnomad NFE exome AF: 0.162

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.153 AC: 223987 AN: 1461810 Hom.: 17785 Cov.: 33 AF XY: 0.155 AC XY: 112624 AN XY: 727222

African (AFR) AF: 0.0930 AC: 3112 AN: 33480

American (AMR) AF: 0.106 AC: 4756 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6659 AN: 26136

East Asian (EAS) AF: 0.183 AC: 7263 AN: 39700

South Asian (SAS) AF: 0.183 AC: 15807 AN: 86258

European-Finnish (FIN) AF: 0.0888 AC: 4744 AN: 53412

Middle Eastern (MID) AF: 0.241 AC: 1389 AN: 5766

European-Non Finnish (NFE) AF: 0.153 AC: 170444 AN: 1111946

Other (OTH) AF: 0.162 AC: 9813 AN: 60388

GnomAD4 genome AF: 0.136 AC: 20645 AN: 152176 Hom.: 1574 Cov.: 32 AF XY: 0.133 AC XY: 9893 AN XY: 74394

African (AFR) AF: 0.0944 AC: 3918 AN: 41512

American (AMR) AF: 0.128 AC: 1960 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 821 AN: 3468

East Asian (EAS) AF: 0.170 AC: 876 AN: 5168

South Asian (SAS) AF: 0.188 AC: 908 AN: 4820

European-Finnish (FIN) AF: 0.0925 AC: 980 AN: 10596

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10654 AN: 67996

Other (OTH) AF: 0.161 AC: 340 AN: 2106

Alfa AF: 0.154 Hom.: 6932

Bravo AF: 0.134

TwinsUK AF: 0.154 AC: 570

ALSPAC AF: 0.158 AC: 609

ESP6500AA AF: 0.0843 AC: 335

ESP6500EA AF: 0.156 AC: 1301

ExAC AF: 0.152 AC: 18389

Asia WGS AF: 0.163 AC: 569 AN: 3478

EpiCase AF: 0.168

EpiControl AF: 0.175

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.52	D
MetaRNN	Benign	0.00098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.15
Sift	Benign	0.094	T
Sift4G	Uncertain	0.020	D
Polyphen		0.98	D
Vest4		0.086
ClinPred		0.021	T
GERP RS		0.67
Varity_R		0.16
gMVP		0.23
Mutation Taster		=97/3	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: rs12674488; hg19: chr8-6338306; COSMIC: COSV107433837;