Genetic Variant CCDC73:p.Val959Ala (chr11-32613442-A-G) – 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_001008391.4(CCDC73):c.2876T>C(p.Val959Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,256 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. 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. V959G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CCDC73
NM_001008391.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.22

Publications

1 publications found

Variant links:

Genes affected

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

CCDC73 links:

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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=0.037310034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC73	NM_001008391.4 link	c.2876T>C	p.Val959Ala	missense_variant	Exon 16 of 18	ENST00000335185.10	NP_001008392.2	Q6ZRK6-1
CCDC73	XM_047427029.1 link	c.2876T>C	p.Val959Ala	missense_variant	Exon 21 of 23		XP_047282985.1
CCDC73	XM_047427030.1 link	c.2876T>C	p.Val959Ala	missense_variant	Exon 16 of 18		XP_047282986.1
CCDC73	XM_047427031.1 link	c.2618T>C	p.Val873Ala	missense_variant	Exon 15 of 17		XP_047282987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC73	ENST00000335185.10 link	c.2876T>C	p.Val959Ala	missense_variant	Exon 16 of 18	2	NM_001008391.4	ENSP00000335325.5		Q6ZRK6-1
CCDC73	ENST00000528333.1 link	c.136-10422T>C		intron_variant	Intron 1 of 1	3		ENSP00000434365.1		H0YDV2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248466

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000292

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:

0.00000206

AC:

AN:

1459256

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725516

show subpopulations

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

African (AFR)

AF:

0.0000299

AC:

AN:

33414

American (AMR)

AF:

0.0000225

AC:

AN:

44452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39648

South Asian (SAS)

AF:

0.00

AC:

AN:

85932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110314

Other (OTH)

AF:

0.00

AC:

AN:

60300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.016

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.0070

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.23

M_CAP

Benign

0.0045

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.49

PhyloP100

-1.2

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.51

REVEL

Benign

0.013

Sift

Benign

0.34

Sift4G

Benign

0.27

Polyphen

0.0020

Vest4

0.071

MutPred

0.23

Loss of stability (P = 0.0098);

MVP

0.030

MPC

0.13

ClinPred

0.097

GERP RS

-11

Varity_R

0.027

gMVP

0.056

Mutation Taster

=97/3

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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chr11-32613442-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over