chr17-65852022-T-C

Variant names:

• chr17-65852022-T-C
• rs373330595
• NM_001199165.4:c.2176A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001199165.4(CEP112):​c.2176A>G​(p.Met726Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,608,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CEP112 NM_001199165.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.885
• Publications: 0 publications found

Genes affected

CEP112 (HGNC:28514): (centrosomal protein 112) This gene encodes a coiled-coil domain containing protein that belongs to the cell division control protein 42 effector protein family. In neurons, it localizes to the cytoplasm of dendrites and is also enriched in the nucleus where it interacts with the RNA polymerase III transcriptional repressor Maf1 to regulate gamma-aminobutyric acid A receptor surface expression. In addition, the protein has been identified as a component of the human centrosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

CEP112 Gene-Disease associations (from GenCC):

• spermatogenic failure 44

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32558447).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199165.4. 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
	CEP112	NM_001199165.4	MANE Select	c.2176A>G	p.Met726Val	missense	Exon 21 of 27	NP_001186094.1	Q8N8E3-1
	CEP112	NM_001353129.2		c.2179A>G	p.Met727Val	missense	Exon 21 of 27	NP_001340058.1
	CEP112	NM_001353127.2		c.2176A>G	p.Met726Val	missense	Exon 21 of 27	NP_001340056.1	Q8N8E3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP112	ENST00000535342.7	TSL:2 MANE Select	c.2176A>G	p.Met726Val	missense	Exon 21 of 27	ENSP00000442784.2	Q8N8E3-1
	CEP112	ENST00000537949.5	TSL:1	c.2050A>G	p.Met684Val	missense	Exon 19 of 25	ENSP00000440775.1	F5GYE8
	CEP112	ENST00000859226.1		c.2275A>G	p.Met759Val	missense	Exon 22 of 28	ENSP00000529285.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456110 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724046

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000604 AC: 2 AN: 33102

American (AMR) AF: 0.00 AC: 0 AN: 43558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 84840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110528

Other (OTH) AF: 0.0000332 AC: 2 AN: 60166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000167064), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

African (AFR) AF: 0.0000724 AC: 3 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.89
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.051
Sift	Uncertain	0.010	D
Sift4G	Benign	0.48	T
Polyphen		0.40	B
Vest4		0.71
MutPred		0.27		Loss of catalytic residue at V722 (P = 0.0151)
MVP		0.21
MPC		0.23
ClinPred		0.80	D
GERP RS		5.2
Varity_R		0.19
gMVP		0.24
Mutation Taster		=93/7	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: rs373330595; hg19: chr17-63848140;