8-6499929-C-T

Variant names:

• chr8-6499929-C-T
• rs35344839
• NM_024596.5:c.2214C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024596.5(MCPH1):​c.2214C>T​(p.Pro738Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P738P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: MCPH1 NM_024596.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003142
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.0740
• Publications: 0 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]

ANGPT2 (HGNC:485): (angiopoietin 2) This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

ANGPT2 Gene-Disease associations (from GenCC):

• lymphatic malformation 10

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

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.2214C>T	p.Pro738Pro	splice_region synonymous	Exon 12 of 14	NP_078872.3	Q8NEM0-1
	ANGPT2	NM_001118887.2	MANE Select	c.*3172G>A		3_prime_UTR	Exon 9 of 9	NP_001112359.1	O15123-3
	MCPH1	NM_001322042.2		c.2214C>T	p.Pro738Pro	splice_region synonymous	Exon 12 of 15	NP_001308971.2	A0A8I5KV10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2214C>T	p.Pro738Pro	splice_region synonymous	Exon 12 of 14	ENSP00000342924.5	Q8NEM0-1
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.*3172G>A		3_prime_UTR	Exon 9 of 9	ENSP00000486858.2	O15123-3
	ANGPT2	ENST00000325203.9	TSL:1	c.*3172G>A		3_prime_UTR	Exon 9 of 9	ENSP00000314897.5	O15123-1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249550 AF XY: 0.0000443

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1460814 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 726790

African (AFR) AF: 0.000179 AC: 6 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111416

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152242 Hom.: 1 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74464

African (AFR) AF: 0.000289 AC: 12 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000818 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Microcephaly 1, primary, autosomal recessive (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.4
DANN	Benign	0.84
PhyloP100		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.086
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35344839; hg19: chr8-6357450;