dbSNP rs371366392: CCDC174:p.Thr47Asn (chr3-14654523-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016474.5(CCDC174):c.140C>A(p.Thr47Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000762 in 1,312,528 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T47S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

CCDC174
NM_016474.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.446

Publications

0 publications found

Variant links:

Genes affected

CCDC174 (HGNC:28033): (coiled-coil domain containing 174) The protein encoded by this gene is found in the nucleus, where it interacts with eukaryotic translation initiation factor 4A, isoform 3. The encoded protein appears to be a part of the exon junction complex, which is involved in RNA processing, translation, and nonsense-mediated mRNA decay. A mutation in this gene has been associated with infantile hypotonia with psychomotor retardation. [provided by RefSeq, Mar 2016]

CCDC174 Gene-Disease associations (from GenCC):

severe hypotonia-psychomotor developmental delay-strabismus-cardiac septal defect syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

CCDC174 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 (MetaRNN=0.06262234).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016474.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC174	NM_016474.5	MANE Select	c.140C>A	p.Thr47Asn	missense	Exon 2 of 11	NP_057558.3
CCDC174	NM_001410719.1		c.140C>A	p.Thr47Asn	missense	Exon 2 of 9	NP_001397648.1	A0A0B4J1R8
CCDC174	NR_135523.2		n.215C>A		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC174	ENST00000383794.7	TSL:1 MANE Select	c.140C>A	p.Thr47Asn	missense	Exon 2 of 11	ENSP00000373304.3	Q6PII3
CCDC174	ENST00000465759.1	TSL:1	n.204C>A		non_coding_transcript_exon	Exon 2 of 7
CCDC174	ENST00000303688.8	TSL:5	c.140C>A	p.Thr47Asn	missense	Exon 2 of 9	ENSP00000302344.7	A0A0B4J1R8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1312528

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

659932

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

29914

American (AMR)

AF:

0.00

AC:

AN:

40874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24816

East Asian (EAS)

AF:

0.00

AC:

AN:

38760

South Asian (SAS)

AF:

0.00

AC:

AN:

79184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4978

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

985700

Other (OTH)

AF:

0.00

AC:

AN:

55264

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.037

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.71

M_CAP

Benign

0.011

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.45

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.43

REVEL

Benign

0.053

Sift

Benign

0.47

Sift4G

Benign

0.42

Polyphen

0.14

Vest4

0.27

MutPred

0.17

Gain of glycosylation at T46 (P = 0.0155)

MVP

0.19

MPC

0.10

ClinPred

0.053

GERP RS

3.6

Varity_R

0.032

gMVP

0.18

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over