8-6642723-C-T

Variant names:

• chr8-6642723-C-T
• rs2433148
• NM_024596.5:c.2453-271C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000344683.10(MCPH1):​c.2453-271C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 506,872 control chromosomes in the GnomAD database, including 4,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1642 hom., cov: 32)
  • Exomes 𝑓: 0.12 (3042 hom.)
• Consequence: MCPH1 ENST00000344683.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0410
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-6642723-C-T is Benign according to our data. Variant chr8-6642723-C-T is described in ClinVar as Benign. ClinVar VariationId is 1227819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000344683.10. 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.2453-271C>T		intron	N/A	NP_078872.3
	MCPH1	NM_001322042.2		c.2595-271C>T		intron	N/A	NP_001308971.2
	MCPH1	NM_001363980.2		c.2174-271C>T		intron	N/A	NP_001350909.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2453-271C>T		intron	N/A	ENSP00000342924.5
	MCPH1	ENST00000521175.2	TSL:3	n.1219C>T		non_coding_transcript_exon	Exon 6 of 7
	MCPH1	ENST00000687324.1		n.1434C>T		non_coding_transcript_exon	Exon 6 of 7

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21403 AN: 152006 Hom.: 1638 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.125 AC: 44206 AN: 354748 Hom.: 3042 Cov.: 0 AF XY: 0.127 AC XY: 24052 AN XY: 189140

African (AFR) AF: 0.200 AC: 2083 AN: 10408

American (AMR) AF: 0.0971 AC: 1712 AN: 17636

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 1470 AN: 10850

East Asian (EAS) AF: 0.133 AC: 2883 AN: 21662

South Asian (SAS) AF: 0.169 AC: 7481 AN: 44378

European-Finnish (FIN) AF: 0.0906 AC: 1721 AN: 18994

Middle Eastern (MID) AF: 0.131 AC: 192 AN: 1464

European-Non Finnish (NFE) AF: 0.116 AC: 24188 AN: 209306

Other (OTH) AF: 0.123 AC: 2476 AN: 20050

GnomAD4 genome AF: 0.141 AC: 21437 AN: 152124 Hom.: 1642 Cov.: 32 AF XY: 0.141 AC XY: 10484 AN XY: 74374

African (AFR) AF: 0.202 AC: 8382 AN: 41474

American (AMR) AF: 0.107 AC: 1637 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 518 AN: 3470

East Asian (EAS) AF: 0.131 AC: 678 AN: 5180

South Asian (SAS) AF: 0.176 AC: 851 AN: 4822

European-Finnish (FIN) AF: 0.0896 AC: 949 AN: 10596

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7955 AN: 67988

Other (OTH) AF: 0.150 AC: 316 AN: 2110

Alfa AF: 0.122 Hom.: 1413

Bravo AF: 0.146

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.47
PhyloP100		-0.041
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: rs2433148; hg19: chr8-6500244;