rs200517168

Variant names:

• chr7-77167765-A-G
• rs200517168
• NM_020879.3:c.97A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020879.3(CCDC146):​c.97A>G​(p.Ile33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 35)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CCDC146 NM_020879.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• Publications: 0 publications found

Genes affected

CCDC146 (HGNC:29296): (coiled-coil domain containing 146) Located in centriole. [provided by Alliance of Genome Resources, Apr 2022]

DTX2P1-UPK3BP1-PMS2P11 (HGNC:42360): (DTX2P1-UPK3BP1-PMS2P11 readthrough, transcribed pseudogene) This locus represents naturally-occurring readthrough transcription spanning multiple pseudogenes: DTX2P1 (DTX2 pseudogene 1), UPK3BP1 (uroplakin 3B pseudogene 1), PMS2P11 (PMS1 homolog 2, mismatch repair system component pseudogene 11). Some transcripts may also extend to PMS2P9 (PMS1 homolog 2, mismatch repair system component pseudogene 9). The readthrough transcripts likely do not encode functional proteins. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017616749).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020879.3. 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
	CCDC146	NM_020879.3	MANE Select	c.97A>G	p.Ile33Val	missense	Exon 2 of 19	NP_065930.2	Q8IYE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC146	ENST00000285871.5	TSL:1 MANE Select	c.97A>G	p.Ile33Val	missense	Exon 2 of 19	ENSP00000285871.4	Q8IYE0-1
	CCDC146	ENST00000890162.1		c.97A>G	p.Ile33Val	missense	Exon 2 of 18	ENSP00000560221.1
	CCDC146	ENST00000415750.5	TSL:4	c.97A>G	p.Ile33Val	missense	Exon 2 of 5	ENSP00000388649.1	C9JRR4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152268 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000576

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

GnomAD2 exomes AF: 0.0000742 AC: 18 AN: 242492 AF XY: 0.0000535

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1459210 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 725874

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

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.000734 AC: 29 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110954

Other (OTH) AF: 0.000183 AC: 11 AN: 60252

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152386 Hom.: 0 Cov.: 35 AF XY: 0.0000268 AC XY: 2 AN XY: 74520

African (AFR) AF: 0.00 AC: 0 AN: 41602

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

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

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000301 Hom.: 0

ExAC AF: 0.0000659 AC: 8

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	0.088
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.14
Sift	Benign	0.15	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.21	B
Vest4		0.21
MVP		0.43
MPC		0.13
ClinPred		0.040	T
GERP RS		1.6
Varity_R		0.033
gMVP		0.063
Mutation Taster		=98/2	polymorphism

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: rs200517168; hg19: chr7-76797082; COSMIC: COSV53553644;