rs60684213

Variant names:

• chr17-80086090-G-A
• rs60684213
• NM_017950.4:c.2323G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80086090-G-A
• chr17-80086090-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017950.4(CCDC40):​c.2323G>A​(p.Val775Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0862 in 1,614,060 control chromosomes in the GnomAD database, including 7,071 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V775V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1255 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5816 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.64
• Publications: 13 publications found

Genes affected

CCDC40 (HGNC:26090): (coiled-coil domain 40 molecular ruler complex subunit) This gene encodes a protein that is necessary for motile cilia function. It functions in correct left-right axis formation by regulating the assembly of the inner dynein arm and the dynein regulatory complexes, which control ciliary beat. Mutations in this gene cause ciliary dyskinesia type 15, a disorder due to defects in cilia motility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

CCDC40 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autoimmune disease

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017687082).
• BP6: Variant 17-80086090-G-A is Benign according to our data. Variant chr17-80086090-G-A is described in ClinVar as Benign. ClinVar VariationId is 162851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017950.4. 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
	CCDC40	NM_017950.4	MANE Select	c.2323G>A	p.Val775Met	missense	Exon 14 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.2323G>A	p.Val775Met	missense	Exon 14 of 18	NP_001230271.1	Q4G0X9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.2323G>A	p.Val775Met	missense	Exon 14 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000574799.5	TSL:1	n.1860G>A		non_coding_transcript_exon	Exon 10 of 16
	CCDC40	ENST00000897784.1		c.2323G>A	p.Val775Met	missense	Exon 14 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17475 AN: 152128 Hom.: 1251 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0645

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0824

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.0819

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.0880 AC: 21937 AN: 249388 AF XY: 0.0886

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.000612

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0855

Gnomad OTH exome AF: 0.0949

GnomAD4 exome AF: 0.0832 AC: 121580 AN: 1461812 Hom.: 5816 Cov.: 32 AF XY: 0.0839 AC XY: 61034 AN XY: 727208

African (AFR) AF: 0.217 AC: 7252 AN: 33476

American (AMR) AF: 0.0559 AC: 2498 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2748 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.0990 AC: 8543 AN: 86252

European-Finnish (FIN) AF: 0.114 AC: 6062 AN: 53406

Middle Eastern (MID) AF: 0.128 AC: 736 AN: 5744

European-Non Finnish (NFE) AF: 0.0795 AC: 88388 AN: 1111986

Other (OTH) AF: 0.0884 AC: 5338 AN: 60390

GnomAD4 genome AF: 0.115 AC: 17488 AN: 152248 Hom.: 1255 Cov.: 32 AF XY: 0.114 AC XY: 8523 AN XY: 74446

African (AFR) AF: 0.207 AC: 8603 AN: 41540

American (AMR) AF: 0.0643 AC: 985 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0825 AC: 398 AN: 4824

European-Finnish (FIN) AF: 0.115 AC: 1215 AN: 10600

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.0819 AC: 5573 AN: 68014

Other (OTH) AF: 0.111 AC: 234 AN: 2112

Alfa AF: 0.0909 Hom.: 1679

Bravo AF: 0.115

TwinsUK AF: 0.0771 AC: 286

ALSPAC AF: 0.0815 AC: 314

ESP6500AA AF: 0.185 AC: 775

ESP6500EA AF: 0.0846 AC: 711

ExAC AF: 0.0915 AC: 11069

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0858

EpiControl AF: 0.0860

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	Primary ciliary dyskinesia 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.035
Sift	Benign	0.15	T
Sift4G	Benign	0.12	T
Polyphen		0.19	B
Vest4		0.080
MPC		0.21
ClinPred		0.0066	T
GERP RS		2.7
Varity_R		0.027
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs60684213; hg19: chr17-78059889; COSMIC: COSV107494471;