rs377599647

Variant names:

• chr17-80036690-C-A
• rs377599647
• NM_017950.4:c.28C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80036690-C-A
• chr17-80036690-C-G
• chr17-80036690-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_017950.4(CCDC40):​c.28C>A​(p.Arg10Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,462,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: CCDC40 NM_017950.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005408
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.592
• Publications: 0 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: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine
• primary ciliary dyskinesia

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

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=0.592 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC40	NM_017950.4	c.28C>A	p.Arg10Arg	splice_region_variant, synonymous_variant	Exon 1 of 20	ENST00000397545.9	NP_060420.2
CCDC40	NM_001243342.2	c.28C>A	p.Arg10Arg	splice_region_variant, synonymous_variant	Exon 1 of 18		NP_001230271.1
CCDC40	NM_001330508.2	c.28C>A	p.Arg10Arg	splice_region_variant, synonymous_variant	Exon 1 of 11		NP_001317437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC40	ENST00000397545.9	c.28C>A	p.Arg10Arg	splice_region_variant, synonymous_variant	Exon 1 of 20	5	NM_017950.4	ENSP00000380679.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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

GnomAD4 exome AF: 0.00000229 AC: 3 AN: 1310546 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 644322

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

African (AFR) AF: 0.0000361 AC: 1 AN: 27724

American (AMR) AF: 0.00 AC: 0 AN: 27080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22900

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 70530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041020

Other (OTH) AF: 0.0000185 AC: 1 AN: 54138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.004626), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74418

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.57
PhyloP100		0.59
PromoterAI		0.036	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.060
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: rs377599647; hg19: chr17-78010489;