Genetic Variant NM_001258306.3:c.233T>C (chr2-131528203-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001258306.3(CCDC74A):c.233T>C(p.Leu78Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L78R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CCDC74A
NM_001258306.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.89

Publications

1 publications found

Variant links:

Genes affected

CCDC74A (HGNC:25197): (coiled-coil domain containing 74A)

CCDC74A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258306.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74A	NM_001258306.3	MANE Select	c.233T>C	p.Leu78Pro	missense	Exon 1 of 8	NP_001245235.1	Q96AQ1-2
CCDC74A	NM_001349042.2		c.233T>C	p.Leu78Pro	missense	Exon 1 of 8	NP_001335971.1
CCDC74A	NM_138770.4		c.233T>C	p.Leu78Pro	missense	Exon 1 of 8	NP_620125.1	Q96AQ1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC74A	ENST00000409856.8	TSL:1 MANE Select	c.233T>C	p.Leu78Pro	missense	Exon 1 of 8	ENSP00000387009.3	Q96AQ1-2
CCDC74A	ENST00000295171.10	TSL:1	c.233T>C	p.Leu78Pro	missense	Exon 1 of 8	ENSP00000295171.6	Q96AQ1-1
CCDC74A	ENST00000467992.6	TSL:1	c.233T>C	p.Leu78Pro	missense	Exon 1 of 7	ENSP00000444610.2	F5GZA4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245696

AF XY:

0.00000748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460718

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111580

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.24

MutationAssessor

Pathogenic

3.0

PhyloP100

3.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.70

MutPred

0.42

Loss of helix (P = 3e-04)

MVP

0.88

MPC

3.1

ClinPred

0.99

GERP RS

2.8

PromoterAI

0.034

Neutral

(source)

Varity_R

0.97

gMVP

0.74

Mutation Taster

=69/31

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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