rs2277136

Variant names:

• chr8-6477687-T-C
• rs2277136
• NM_024596.5:c.1973+56T>C

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.1973+56T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,477,612 control chromosomes in the GnomAD database, including 13,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1369 hom., cov: 33)
  • Exomes 𝑓: 0.13 (11898 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.209
• 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=-0.86).
• BP6: Variant 8-6477687-T-C is Benign according to our data. Variant chr8-6477687-T-C is described in ClinVar as Benign. ClinVar VariationId is 1225800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1973+56T>C		intron_variant	Intron 10 of 13	ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCPH1	ENST00000344683.10	c.1973+56T>C		intron_variant	Intron 10 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19592 AN: 152140 Hom.: 1367 Cov.: 33

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.130 AC: 171721 AN: 1325354 Hom.: 11898 AF XY: 0.132 AC XY: 88053 AN XY: 666744

African (AFR) AF: 0.132 AC: 4034 AN: 30614

American (AMR) AF: 0.0963 AC: 4286 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5801 AN: 25334

East Asian (EAS) AF: 0.186 AC: 7238 AN: 38980

South Asian (SAS) AF: 0.182 AC: 15166 AN: 83416

European-Finnish (FIN) AF: 0.0603 AC: 3139 AN: 52056

Middle Eastern (MID) AF: 0.239 AC: 1279 AN: 5342

European-Non Finnish (NFE) AF: 0.124 AC: 122749 AN: 989206

Other (OTH) AF: 0.144 AC: 8029 AN: 55900

GnomAD4 genome AF: 0.129 AC: 19600 AN: 152258 Hom.: 1369 Cov.: 33 AF XY: 0.127 AC XY: 9440 AN XY: 74462

African (AFR) AF: 0.128 AC: 5305 AN: 41538

American (AMR) AF: 0.119 AC: 1827 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 750 AN: 3466

East Asian (EAS) AF: 0.172 AC: 893 AN: 5188

South Asian (SAS) AF: 0.193 AC: 929 AN: 4820

European-Finnish (FIN) AF: 0.0618 AC: 656 AN: 10616

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.129 AC: 8784 AN: 68012

Other (OTH) AF: 0.151 AC: 319 AN: 2114

Alfa AF: 0.126 Hom.: 214

Bravo AF: 0.130

Asia WGS AF: 0.167 AC: 582 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

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	-0.86
CADD	Benign	1.0
DANN	Benign	0.77
PhyloP100		-0.21
PromoterAI		0.0095	Neutral
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: rs2277136; hg19: chr8-6335208; COSMIC: COSV107433836; COSMIC: COSV107433836;