19-11350931-G-A

Variant names:

• chr19-11350931-G-A
• rs761124235
• NM_001080503.3:c.350G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080503.3(CCDC159):​c.350G>A​(p.Arg117His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 1,554,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: CCDC159 NM_001080503.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.131
• Publications: 0 publications found

Genes affected

CCDC159 (HGNC:26996): (coiled-coil domain containing 159)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040218264).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080503.3. 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
	CCDC159	NM_001080503.3	MANE Select	c.350G>A	p.Arg117His	missense	Exon 5 of 11	NP_001073972.2	P0C7I6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC159	ENST00000458408.6	TSL:5 MANE Select	c.350G>A	p.Arg117His	missense	Exon 5 of 11	ENSP00000402239.1	P0C7I6-2
	CCDC159	ENST00000853370.1		c.350G>A	p.Arg117His	missense	Exon 5 of 11	ENSP00000523429.1
	CCDC159	ENST00000588790.5	TSL:5	c.350G>A	p.Arg117His	missense	Exon 7 of 13	ENSP00000468232.1	P0C7I6-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.0000190 AC: 3 AN: 157710 AF XY: 0.0000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000647

Gnomad NFE exome AF: 0.0000322

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000499 AC: 7 AN: 1401910 Hom.: 0 Cov.: 32 AF XY: 0.00000434 AC XY: 3 AN XY: 691774

African (AFR) AF: 0.00 AC: 0 AN: 31822

American (AMR) AF: 0.0000278 AC: 1 AN: 35974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 36030

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00000370 AC: 4 AN: 1080972

Other (OTH) AF: 0.0000172 AC: 1 AN: 58138

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.000196 AC: 3 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000437044), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000184 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.13
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.047
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Vest4		0.068
MVP		0.030
MPC		0.13
ClinPred		0.046	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.041
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs761124235; hg19: chr19-11461607;