NM_018131.5:c.295A>G

Variant names:

• chr10-93503224-A-G
• rs7080916
• NM_018131.5:c.295A>G

Variant summary

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

The NM_018131.5(CEP55):​c.295A>G​(p.Thr99Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,614,080 control chromosomes in the GnomAD database, including 802,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T99S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.99 (74083 hom., cov: 30)
  • Exomes 𝑓: 1.0 (728751 hom.)
• Consequence: CEP55 NM_018131.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.257
• Publications: 27 publications found

Genes affected

CEP55 (HGNC:1161): (centrosomal protein 55) Enables identical protein binding activity. Involved in cranial skeletal system development; establishment of protein localization; and midbody abscission. Acts upstream of or within mitotic cytokinesis. Located in Flemming body; centriolar satellite; and plasma membrane. Implicated in multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly. [provided by Alliance of Genome Resources, Apr 2022]

CEP55 Gene-Disease associations (from GenCC):

• multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.549749E-7).
• BP6: Variant 10-93503224-A-G is Benign according to our data. Variant chr10-93503224-A-G is described in ClinVar as Benign. ClinVar VariationId is 1636324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018131.5. 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
	CEP55	NM_018131.5	MANE Select	c.295A>G	p.Thr99Ala	missense	Exon 3 of 9	NP_060601.4
	CEP55	NM_001127182.2		c.295A>G	p.Thr99Ala	missense	Exon 3 of 9	NP_001120654.2	Q53EZ4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP55	ENST00000371485.8	TSL:1 MANE Select	c.295A>G	p.Thr99Ala	missense	Exon 3 of 9	ENSP00000360540.3	Q53EZ4-1
	CEP55	ENST00000897343.1		c.295A>G	p.Thr99Ala	missense	Exon 3 of 9	ENSP00000567402.1
	CEP55	ENST00000912346.1		c.295A>G	p.Thr99Ala	missense	Exon 3 of 9	ENSP00000582405.1

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150056 AN: 152140 Hom.: 74027 Cov.: 30

Gnomad AFR AF: 0.952

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.989

GnomAD2 exomes AF: 0.996 AC: 250477 AN: 251444 AF XY: 0.997

Gnomad AFR exome AF: 0.949

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1459609 AN: 1461822 Hom.: 728751 Cov.: 51 AF XY: 0.999 AC XY: 726194 AN XY: 727214

African (AFR) AF: 0.952 AC: 31865 AN: 33476

American (AMR) AF: 0.997 AC: 44606 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26132 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39684 AN: 39688

South Asian (SAS) AF: 1.00 AC: 86246 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53418 AN: 53418

Middle Eastern (MID) AF: 0.995 AC: 5740 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111740 AN: 1111970

Other (OTH) AF: 0.996 AC: 60178 AN: 60390

GnomAD4 genome AF: 0.986 AC: 150171 AN: 152258 Hom.: 74083 Cov.: 30 AF XY: 0.987 AC XY: 73467 AN XY: 74438

African (AFR) AF: 0.952 AC: 39557 AN: 41532

American (AMR) AF: 0.996 AC: 15217 AN: 15284

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4821 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68015 AN: 68036

Other (OTH) AF: 0.990 AC: 2092 AN: 2114

Alfa AF: 0.995 Hom.: 180689

Bravo AF: 0.984

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.953 AC: 4201

ESP6500EA AF: 1.00 AC: 8598

ExAC AF: 0.995 AC: 120829

Asia WGS AF: 0.995 AC: 3461 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.44
DANN	Benign	0.39
DEOGEN2	Benign	0.00021	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-0.26
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.0050
Sift	Benign	0.45	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.14
ClinPred		0.00090	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.031
Mutation Taster		=99/1	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: rs7080916; hg19: chr10-95262981; COSMIC: COSV107473650; COSMIC: COSV107473650;