NM_024596.5:c.-5C>A

Variant names:

• chr8-6406663-C-A
• rs771277920
• NM_024596.5:c.-5C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024596.5(MCPH1):​c.-5C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,938 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MCPH1 NM_024596.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20
• 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]

MCPH1-DT (HGNC:55599): (MCPH1 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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.-5C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_024596.5	MANE Select	c.-5C>A		5_prime_UTR	Exon 1 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.-5C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-5C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000519480.6	TSL:1	c.-5C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000430962.1	Q8NEM0-3
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.-5C>A		5_prime_UTR	Exon 1 of 14	ENSP00000342924.5	Q8NEM0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459938 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726260

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111504

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.0
DANN	Benign	0.84
PhyloP100		-1.2
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs771277920; hg19: chr8-6264184;