rs369127299

Variant names:

• chr8-6621634-C-T
• rs369127299
• NM_024596.5:c.2395C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-6621634-C-T
• chr8-6621634-C-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_024596.5(MCPH1):​c.2395C>T​(p.Pro799Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,614,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P799P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: MCPH1 NM_024596.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.903
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048956037).
• BP6: Variant 8-6621634-C-T is Benign according to our data. Variant chr8-6621634-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 363563.
• BS2: High Homozygotes in GnomAdExome4 at 2 Unknown,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.2395C>T	p.Pro799Ser	missense	Exon 13 of 14	NP_078872.3	Q8NEM0-1
	MCPH1	NM_001322042.2		c.2395C>T	p.Pro799Ser	missense	Exon 13 of 15	NP_001308971.2	A0A8I5KV10
	MCPH1	NM_001410917.1		c.2395C>T	p.Pro799Ser	missense	Exon 13 of 14	NP_001397846.1	A0A8I5KPV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2395C>T	p.Pro799Ser	missense	Exon 13 of 14	ENSP00000342924.5	Q8NEM0-1
	MCPH1	ENST00000692836.1		c.2395C>T	p.Pro799Ser	missense	Exon 13 of 13	ENSP00000509971.1	A0A8I5KX36
	MCPH1	ENST00000689348.1		c.2395C>T	p.Pro799Ser	missense	Exon 13 of 15	ENSP00000509554.1	A0A8I5KV10

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000228 AC: 57 AN: 249486 AF XY: 0.000325

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000150 AC: 219 AN: 1461890 Hom.: 2 Cov.: 50 AF XY: 0.000180 AC XY: 131 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000818 AC: 91 AN: 1112008

Other (OTH) AF: 0.000199 AC: 12 AN: 60396

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74474

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000223 AC: 27

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.31	N
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.049	T
MetaSVM	Uncertain	-0.010	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.90
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.33
Sift	Benign	0.15	T
Sift4G	Uncertain	0.048	D
Polyphen		0.61	P
Vest4		0.18
MVP		0.84
ClinPred		0.045	T
GERP RS		3.3
Varity_R		0.18
gMVP		0.32
Mutation Taster		=98/2	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: rs369127299; hg19: chr8-6479155;