rs17077744

Variant names:

• chr8-6642980-C-T
• rs17077744
• NM_024596.5:c.2453-14C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024596.5(MCPH1):​c.2453-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,320 control chromosomes in the GnomAD database, including 35 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 0.0086 (22 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (13 hom.)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.280
• Publications: 2 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-AS1 (HGNC:51655): (MCPH1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-6642980-C-T is Benign according to our data. Variant chr8-6642980-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158862.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00861 (1311/152312) while in subpopulation AFR AF = 0.0299 (1243/41568). AF 95% confidence interval is 0.0285. There are 22 homozygotes in GnomAd4. There are 624 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2453-14C>T		intron	N/A	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2595-14C>T		intron	N/A	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001363980.2		c.2174-14C>T		intron	N/A	NP_001350909.1	A0A8I5KR97

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2453-14C>T		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000689348.1		c.2595-14C>T		intron	N/A	ENSP00000509554.1	A0A8I5KV10
	MCPH1	ENST00000949609.1		c.2375-14C>T		intron	N/A	ENSP00000619668.1

Frequencies

GnomAD3 genomes AF: 0.00856 AC: 1303 AN: 152194 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00209 AC: 522 AN: 249274 AF XY: 0.00166

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000707

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000821 AC: 1199 AN: 1461008 Hom.: 13 Cov.: 29 AF XY: 0.000733 AC XY: 533 AN XY: 726856

African (AFR) AF: 0.0281 AC: 938 AN: 33406

American (AMR) AF: 0.00119 AC: 53 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111382

Other (OTH) AF: 0.00189 AC: 114 AN: 60372

GnomAD4 genome AF: 0.00861 AC: 1311 AN: 152312 Hom.: 22 Cov.: 33 AF XY: 0.00838 AC XY: 624 AN XY: 74472

African (AFR) AF: 0.0299 AC: 1243 AN: 41568

American (AMR) AF: 0.00307 AC: 47 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00451 Hom.: 3

Bravo AF: 0.00954

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Microcephaly 1, primary, autosomal recessive (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.0
DANN	Benign	0.67
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17077744; hg19: chr8-6500501;