8-6445450-C-T

Variant names:

• chr8-6445450-C-T
• rs41313954
• NM_024596.5:c.1728C>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.1728C>T​(p.Gly576Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,614,150 control chromosomes in the GnomAD database, including 1,801 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. G576G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (239 hom., cov: 33)
  • Exomes 𝑓: 0.020 (1562 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0150
• Publications: 6 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=-0.75).
• BP6: Variant 8-6445450-C-T is Benign according to our data. Variant chr8-6445450-C-T is described in ClinVar as Benign. ClinVar VariationId is 158825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.015 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 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.1728C>T	p.Gly576Gly	synonymous	Exon 8 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.1728C>T	p.Gly576Gly	synonymous	Exon 8 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.1728C>T	p.Gly576Gly	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.1728C>T	p.Gly576Gly	synonymous	Exon 8 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.1728C>T	p.Gly576Gly	synonymous	Exon 8 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000692836.1		c.1728C>T	p.Gly576Gly	synonymous	Exon 8 of 13	ENSP00000509971.1	A0A8I5KX36

Frequencies

GnomAD3 genomes AF: 0.0334 AC: 5083 AN: 152164 Hom.: 235 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00575

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0431 AC: 10750 AN: 249226 AF XY: 0.0437

Gnomad AFR exome AF: 0.0538

Gnomad AMR exome AF: 0.0316

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.212

Gnomad FIN exome AF: 0.0429

Gnomad NFE exome AF: 0.00720

Gnomad OTH exome AF: 0.0268

GnomAD4 exome AF: 0.0203 AC: 29685 AN: 1461868 Hom.: 1562 Cov.: 44 AF XY: 0.0222 AC XY: 16138 AN XY: 727230

African (AFR) AF: 0.0503 AC: 1685 AN: 33478

American (AMR) AF: 0.0303 AC: 1356 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 83 AN: 26136

East Asian (EAS) AF: 0.196 AC: 7787 AN: 39698

South Asian (SAS) AF: 0.100 AC: 8630 AN: 86258

European-Finnish (FIN) AF: 0.0422 AC: 2254 AN: 53400

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.00536 AC: 5965 AN: 1112010

Other (OTH) AF: 0.0309 AC: 1864 AN: 60396

GnomAD4 genome AF: 0.0335 AC: 5105 AN: 152282 Hom.: 239 Cov.: 33 AF XY: 0.0368 AC XY: 2742 AN XY: 74468

African (AFR) AF: 0.0507 AC: 2108 AN: 41544

American (AMR) AF: 0.0250 AC: 382 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.218 AC: 1127 AN: 5178

South Asian (SAS) AF: 0.108 AC: 523 AN: 4826

European-Finnish (FIN) AF: 0.0459 AC: 487 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00575 AC: 391 AN: 68034

Other (OTH) AF: 0.0340 AC: 72 AN: 2116

Alfa AF: 0.0141 Hom.: 196

Bravo AF: 0.0313

Asia WGS AF: 0.143 AC: 498 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00492

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-0.015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs41313954; hg19: chr8-6302971; COSMIC: COSV60915371;