NM_024596.5:c.1973+396T>C

Variant names:

• chr8-6478027-T-C
• rs2515591
• NM_024596.5:c.1973+396T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):​c.1973+396T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0658 in 152,292 control chromosomes in the GnomAD database, including 446 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.066 (446 hom., cov: 33)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCPH1	NM_024596.5	c.1973+396T>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+396T>C		intron_variant	Intron 10 of 13	1	NM_024596.5	ENSP00000342924.5

Frequencies

GnomAD3 genomes AF: 0.0658 AC: 10019 AN: 152174 Hom.: 447 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0328

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0979

Gnomad OTH AF: 0.0697

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0658 AC: 10016 AN: 152292 Hom.: 446 Cov.: 33 AF XY: 0.0644 AC XY: 4799 AN XY: 74476

African (AFR) AF: 0.0179 AC: 746 AN: 41572

American (AMR) AF: 0.0567 AC: 867 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 139 AN: 3468

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.0332 AC: 160 AN: 4820

European-Finnish (FIN) AF: 0.118 AC: 1253 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0978 AC: 6654 AN: 68012

Other (OTH) AF: 0.0690 AC: 146 AN: 2116

Alfa AF: 0.0744 Hom.: 365

Bravo AF: 0.0601

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		2.7
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: rs2515591; hg19: chr8-6335548;