rs75175362

Positions:

• chr19-46411670-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032040.5(CCDC8):​c.1141G>A​(p.Asp381Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.056 in 1,584,976 control chromosomes in the GnomAD database, including 3,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (278 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2844 hom.)
• Consequence: CCDC8 NM_032040.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.104

Genes affected

CCDC8 (HGNC:25367): (coiled-coil domain containing 8) This gene encodes a coiled-coil domain-containing protein. The encoded protein functions as a cofactor required for p53-mediated apoptosis following DNA damage, and may also play a role in growth through interactions with the cytoskeletal adaptor protein obscurin-like 1. Mutations in this gene are a cause of 3M syndrome-3 (3M3). [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.3327293E-4).
• BP6: Variant 19-46411670-C-T is Benign according to our data. Variant chr19-46411670-C-T is described in ClinVar as [Benign]. Clinvar id is 262003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-46411670-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC8	NM_032040.5	c.1141G>A	p.Asp381Asn	missense_variant	1/1	ENST00000307522.5	NP_114429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC8	ENST00000307522.5	c.1141G>A	p.Asp381Asn	missense_variant	1/1	6	NM_032040.5	ENSP00000303158.3
CCDC8	ENST00000697726.1	c.1351G>A	p.Asp451Asn	missense_variant	1/1			ENSP00000513420.1

Frequencies

GnomAD3 genomes AF: 0.0528 AC: 8030 AN: 152012 Hom.: 281 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0493

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.0804

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0489

Gnomad OTH AF: 0.0489

GnomAD3 exomes AF: 0.0715 AC: 17985 AN: 251490 Hom.: 957 AF XY: 0.0701 AC XY: 9532 AN XY: 135920

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.0323

Gnomad EAS exome AF: 0.192

Gnomad SAS exome AF: 0.0734

Gnomad FIN exome AF: 0.0995

Gnomad NFE exome AF: 0.0495

Gnomad OTH exome AF: 0.0591

GnomAD4 exome AF: 0.0563 AC: 80732 AN: 1432846 Hom.: 2844 Cov.: 33 AF XY: 0.0568 AC XY: 40365 AN XY: 710944

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.0919

Gnomad4 ASJ exome AF: 0.0324

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.0768

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0491

Gnomad4 OTH exome AF: 0.0584

GnomAD4 genome AF: 0.0528 AC: 8030 AN: 152130 Hom.: 278 Cov.: 32 AF XY: 0.0554 AC XY: 4119 AN XY: 74376

Gnomad4 AFR AF: 0.0291

Gnomad4 AMR AF: 0.0494

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.0800

Gnomad4 FIN AF: 0.107

Gnomad4 NFE AF: 0.0489

Gnomad4 OTH AF: 0.0503

Alfa AF: 0.0500 Hom.: 445

Bravo AF: 0.0499

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0493 AC: 190

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.0466 AC: 401

ExAC AF: 0.0695 AC: 8439

Asia WGS AF: 0.131 AC: 455 AN: 3478

EpiCase AF: 0.0443

EpiControl AF: 0.0440

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0024	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.35	.;T
MetaRNN	Benign	0.00083	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.68	.;N
REVEL	Benign	0.043
Sift	Benign	0.15	.;T
Sift4G	Benign	0.40	.;T
Polyphen		0.36	B;B
Vest4		0.015
MPC		0.41
ClinPred		0.0016	T
GERP RS		1.8
Varity_R		0.027
gMVP		0.076

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

LitVar

Other links and lift over

dbSNP: rs75175362; hg19: chr19-46914927; COSMIC: COSV56773116;