8-6436159-C-T

Variant names:

• chr8-6436159-C-T
• rs139607465
• NM_024596.5:c.433C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_024596.5(MCPH1):​c.433C>T​(p.Leu145Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,612,672 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: MCPH1 NM_024596.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.0170
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-6436159-C-T is Benign according to our data. Variant chr8-6436159-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167285.
• BP7: Synonymous conserved (PhyloP=0.017 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.433C>T	p.Leu145Leu	synonymous	Exon 5 of 14	NP_078872.3
	MCPH1	NM_001322042.2		c.433C>T	p.Leu145Leu	synonymous	Exon 5 of 15	NP_001308971.2
	MCPH1	NM_001410917.1		c.433C>T	p.Leu145Leu	synonymous	Exon 5 of 14	NP_001397846.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.433C>T	p.Leu145Leu	synonymous	Exon 5 of 14	ENSP00000342924.5
	MCPH1	ENST00000519480.6	TSL:1	c.433C>T	p.Leu145Leu	synonymous	Exon 5 of 8	ENSP00000430962.1
	MCPH1	ENST00000692836.1		c.433C>T	p.Leu145Leu	synonymous	Exon 5 of 13	ENSP00000509971.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00129 AC: 321 AN: 249014 AF XY: 0.00121

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00188 AC: 2740 AN: 1460352 Hom.: 2 Cov.: 31 AF XY: 0.00177 AC XY: 1283 AN XY: 726480

African (AFR) AF: 0.000359 AC: 12 AN: 33436

American (AMR) AF: 0.00195 AC: 87 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86094

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53314

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5440

European-Non Finnish (NFE) AF: 0.00226 AC: 2508 AN: 1111372

Other (OTH) AF: 0.00216 AC: 130 AN: 60304

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74476

African (AFR) AF: 0.000457 AC: 19 AN: 41584

American (AMR) AF: 0.00261 AC: 40 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00237 AC: 161 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.00156

EpiCase AF: 0.00229

EpiControl AF: 0.00279

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	MCPH1-related disorder (1)
-	1	-	Microcephaly 1, primary, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.1
DANN	Benign	0.57
PhyloP100		0.017
Mutation Taster		=100/0	polymorphism

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: rs139607465; hg19: chr8-6293680;