rs2584

Variant names:

• chr8-6445504-G-A
• rs2584
• NM_024596.5:c.1782G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-6445504-G-A
• chr8-6445504-G-C
• chr8-6445504-G-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.1782G>A​(p.Thr594Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,610,700 control chromosomes in the GnomAD database, including 81,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5542 hom., cov: 34)
  • Exomes 𝑓: 0.31 (75794 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.75
• Publications: 25 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-6445504-G-A is Benign according to our data. Variant chr8-6445504-G-A is described in ClinVar as Benign. ClinVar VariationId is 158827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 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.1782G>A	p.Thr594Thr	synonymous	Exon 8 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.1782G>A	p.Thr594Thr	synonymous	Exon 8 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.1782G>A	p.Thr594Thr	synonymous	Exon 8 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.1782G>A	p.Thr594Thr	synonymous	Exon 8 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.1782G>A	p.Thr594Thr	synonymous	Exon 8 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.1782G>A	p.Thr594Thr	synonymous	Exon 8 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36021 AN: 152082 Hom.: 5542 Cov.: 34

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.0264

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.217

GnomAD2 exomes AF: 0.262 AC: 64266 AN: 245124 AF XY: 0.261

Gnomad AFR exome AF: 0.0514

Gnomad AMR exome AF: 0.281

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.0227

Gnomad FIN exome AF: 0.357

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.310 AC: 452485 AN: 1458500 Hom.: 75794 Cov.: 40 AF XY: 0.306 AC XY: 221953 AN XY: 725332

African (AFR) AF: 0.0490 AC: 1623 AN: 33110

American (AMR) AF: 0.276 AC: 12183 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5316 AN: 26038

East Asian (EAS) AF: 0.0310 AC: 1232 AN: 39680

South Asian (SAS) AF: 0.139 AC: 11903 AN: 85404

European-Finnish (FIN) AF: 0.362 AC: 19215 AN: 53136

Middle Eastern (MID) AF: 0.155 AC: 889 AN: 5728

European-Non Finnish (NFE) AF: 0.345 AC: 383643 AN: 1111050

Other (OTH) AF: 0.274 AC: 16481 AN: 60198

GnomAD4 genome AF: 0.237 AC: 36023 AN: 152200 Hom.: 5542 Cov.: 34 AF XY: 0.233 AC XY: 17318 AN XY: 74404

African (AFR) AF: 0.0613 AC: 2549 AN: 41554

American (AMR) AF: 0.261 AC: 3994 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 787 AN: 3470

East Asian (EAS) AF: 0.0264 AC: 137 AN: 5186

South Asian (SAS) AF: 0.122 AC: 590 AN: 4832

European-Finnish (FIN) AF: 0.357 AC: 3767 AN: 10550

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23374 AN: 67994

Other (OTH) AF: 0.215 AC: 454 AN: 2114

Alfa AF: 0.298 Hom.: 22188

Bravo AF: 0.225

Asia WGS AF: 0.0750 AC: 264 AN: 3478

EpiCase AF: 0.315

EpiControl AF: 0.317

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.43
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2584; hg19: chr8-6303025; COSMIC: COSV60913176;