rs1550697

Variant names:

• chr8-6409253-G-A
• rs1550697
• NM_024596.5:c.23-26G>A

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.23-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 1,569,786 control chromosomes in the GnomAD database, including 51,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (10445 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40994 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.36
• Publications: 8 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: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 8-6409253-G-A is Benign according to our data. Variant chr8-6409253-G-A is described in ClinVar as Benign. ClinVar VariationId is 158854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.23-26G>A		intron_variant	Intron 1 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.23-26G>A		intron_variant	Intron 1 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49785 AN: 151902 Hom.: 10413 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.311

GnomAD2 exomes AF: 0.251 AC: 62496 AN: 249246 AF XY: 0.246

Gnomad AFR exome AF: 0.614

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.304

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.230 AC: 325397 AN: 1417766 Hom.: 40994 Cov.: 24 AF XY: 0.230 AC XY: 162640 AN XY: 708232

African (AFR) AF: 0.619 AC: 20185 AN: 32610

American (AMR) AF: 0.226 AC: 10073 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 8386 AN: 25854

East Asian (EAS) AF: 0.292 AC: 11516 AN: 39480

South Asian (SAS) AF: 0.265 AC: 22639 AN: 85322

European-Finnish (FIN) AF: 0.123 AC: 6541 AN: 53352

Middle Eastern (MID) AF: 0.366 AC: 2088 AN: 5702

European-Non Finnish (NFE) AF: 0.213 AC: 228678 AN: 1071830

Other (OTH) AF: 0.259 AC: 15291 AN: 58962

GnomAD4 genome AF: 0.328 AC: 49861 AN: 152020 Hom.: 10445 Cov.: 32 AF XY: 0.321 AC XY: 23876 AN XY: 74330

African (AFR) AF: 0.602 AC: 24923 AN: 41390

American (AMR) AF: 0.268 AC: 4100 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1571 AN: 5166

South Asian (SAS) AF: 0.275 AC: 1325 AN: 4822

European-Finnish (FIN) AF: 0.123 AC: 1303 AN: 10582

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14606 AN: 67998

Other (OTH) AF: 0.310 AC: 654 AN: 2110

Alfa AF: 0.256 Hom.: 20541

Bravo AF: 0.349

Asia WGS AF: 0.297 AC: 1036 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Microcephaly 1, primary, autosomal recessive Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.81
DANN	Benign	0.84
PhyloP100		1.4
Mutation Taster		=100/0	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: rs1550697; hg19: chr8-6266774;