rs150615436

Variant names:

• chr17-80047357-G-A
• rs150615436
• NM_017950.4:c.631G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80047357-G-A
• chr17-80047357-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017950.4(CCDC40):​c.631G>A​(p.Asp211Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,613,708 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (9 hom.)
• Consequence: CCDC40 NM_017950.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.880
• Publications: 4 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

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

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000289689 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028919578).
• BP6: Variant 17-80047357-G-A is Benign according to our data. Variant chr17-80047357-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00388 (591/152300) while in subpopulation AFR AF = 0.0126 (524/41562). AF 95% confidence interval is 0.0117. There are 4 homozygotes in GnomAd4. There are 297 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

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.631G>A	p.Asp211Asn	missense	Exon 4 of 20	NP_060420.2
	CCDC40	NM_001243342.2		c.631G>A	p.Asp211Asn	missense	Exon 4 of 18	NP_001230271.1	Q4G0X9-2
	CCDC40	NM_001330508.2		c.631G>A	p.Asp211Asn	missense	Exon 4 of 11	NP_001317437.1	Q4G0X9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC40	ENST00000397545.9	TSL:5 MANE Select	c.631G>A	p.Asp211Asn	missense	Exon 4 of 20	ENSP00000380679.4	Q4G0X9-1
	CCDC40	ENST00000374876.4	TSL:1	c.631G>A	p.Asp211Asn	missense	Exon 4 of 9	ENSP00000364010.4	Q4G0X9-5
	CCDC40	ENST00000897784.1		c.631G>A	p.Asp211Asn	missense	Exon 4 of 21	ENSP00000567843.1

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 588 AN: 152182 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00114 AC: 282 AN: 248048 AF XY: 0.000957

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000900

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000577 AC: 843 AN: 1461408 Hom.: 9 Cov.: 33 AF XY: 0.000516 AC XY: 375 AN XY: 727012

African (AFR) AF: 0.0142 AC: 475 AN: 33478

American (AMR) AF: 0.00123 AC: 55 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000743 AC: 64 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5754

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111866

Other (OTH) AF: 0.00156 AC: 94 AN: 60374

GnomAD4 genome AF: 0.00388 AC: 591 AN: 152300 Hom.: 4 Cov.: 33 AF XY: 0.00399 AC XY: 297 AN XY: 74480

African (AFR) AF: 0.0126 AC: 524 AN: 41562

American (AMR) AF: 0.00307 AC: 47 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00148 Hom.: 2

Bravo AF: 0.00467

ESP6500AA AF: 0.0119 AC: 49

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.00129 AC: 156

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	2	Primary ciliary dyskinesia 15 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00055	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.88
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.024
Sift	Benign	0.081	T
Sift4G	Benign	0.25	T
Polyphen		0.43	B
Vest4		0.14
MVP		0.12
MPC		0.17
ClinPred		0.0042	T
GERP RS		0.63
Varity_R		0.036
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150615436; hg19: chr17-78021156; COSMIC: COSV53897791; COSMIC: COSV53897791;