Genetic Variant NM_001008391.4:c.2959A>C (chr11-32611203-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_001008391.4(CCDC73):c.2959A>C(p.Lys987Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CCDC73
NM_001008391.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Publications

1 publications found

Variant links:

Genes affected

CCDC73 (HGNC:23261): (coiled-coil domain containing 73)

CCDC73 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.03427905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC73	NM_001008391.4 link	c.2959A>C	p.Lys987Gln	missense_variant	Exon 17 of 18	ENST00000335185.10	NP_001008392.2	Q6ZRK6-1
CCDC73	XM_047427029.1 link	c.2959A>C	p.Lys987Gln	missense_variant	Exon 22 of 23		XP_047282985.1
CCDC73	XM_047427030.1 link	c.2959A>C	p.Lys987Gln	missense_variant	Exon 17 of 18		XP_047282986.1
CCDC73	XM_047427031.1 link	c.2701A>C	p.Lys901Gln	missense_variant	Exon 16 of 17		XP_047282987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC73	ENST00000335185.10 link	c.2959A>C	p.Lys987Gln	missense_variant	Exon 17 of 18	2	NM_001008391.4	ENSP00000335325.5		Q6ZRK6-1
CCDC73	ENST00000528333.1 link	c.136-8183A>C		intron_variant	Intron 1 of 1	3		ENSP00000434365.1		H0YDV2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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

GnomAD2 exomes

AF:

0.0000321

AC:

AN:

249446

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461322

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726990

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33464

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111548

Other (OTH)

AF:

0.0000166

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000171

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000531

AC:

AN:

41460

American (AMR)

AF:

0.000262

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000466

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00108

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2959A>C (p.K987Q) alteration is located in exon 17 (coding exon 16) of the CCDC73 gene. This alteration results from a A to C substitution at nucleotide position 2959, causing the lysine (K) at amino acid position 987 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0062

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.58

M_CAP

Benign

0.0022

MetaRNN

Benign

0.034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

1.6

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.77

REVEL

Benign

0.019

Sift

Uncertain

0.018

Sift4G

Benign

0.26

Polyphen

0.020

Vest4

0.22

MVP

0.12

MPC

0.31

ClinPred

0.031

GERP RS

2.0

Varity_R

0.12

gMVP

0.12

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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NM_001008391.4:c.2959A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over