9-35660646-C-T

Variant names:

• chr9-35660646-C-T
• rs151241381
• NM_174923.3:c.409C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_174923.3(CCDC107):​c.409C>T​(p.Arg137Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CCDC107 NM_174923.3 missense, splice_region
• Scores: Splicing: ADA: 0.05758
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.977

Genes affected

CCDC107 (HGNC:28465): (coiled-coil domain containing 107) This gene encodes a membrane protein which contains a coiled-coil domain in the central region. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

ARHGEF39 (HGNC:25909): (Rho guanine nucleotide exchange factor 39) Predicted to enable guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell migration. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025739402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC107	NM_174923.3	c.409C>T	p.Arg137Cys	missense_variant, splice_region_variant	Exon 4 of 5	ENST00000426546.7	NP_777583.2
ARHGEF39	NM_032818.3	c.*1341G>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000378387.4	NP_116207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC107	ENST00000426546.7	c.409C>T	p.Arg137Cys	missense_variant, splice_region_variant	Exon 4 of 5	1	NM_174923.3	ENSP00000414964.2
ARHGEF39	ENST00000378387	c.*1341G>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_032818.3	ENSP00000367638.3

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 43 AN: 251438 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000131 AC: 192 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 88 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409C>T (p.R137C) alteration is located in exon 4 (coding exon 4) of the CCDC107 gene. This alteration results from a C to T substitution at nucleotide position 409, causing the arginine (R) at amino acid position 137 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0026	.;T;.
Eigen	Benign	0.027
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.065	T;T;D
Sift4G	Benign	0.098	T;T;D
Polyphen		0.032	.;B;B
Vest4		0.39
MVP		0.38
MPC		0.33
ClinPred		0.10	T
GERP RS		3.1
Varity_R		0.043
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.058
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.080		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: rs151241381; hg19: chr9-35660643; COSMIC: COSV100526182; COSMIC: COSV100526182;