2-131528005-C-G

Variant names:

• chr2-131528005-C-G
• rs767296333
• NM_001258306.3:c.35C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258306.3(CCDC74A):​c.35C>G​(p.Pro12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P12S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC74A NM_001258306.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0630
• Publications: 0 publications found

Genes affected

CCDC74A (HGNC:25197): (coiled-coil domain containing 74A)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21103531).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258306.3. 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
	CCDC74A	NM_001258306.3	MANE Select	c.35C>G	p.Pro12Arg	missense	Exon 1 of 8	NP_001245235.1	Q96AQ1-2
	CCDC74A	NM_001349042.2		c.35C>G	p.Pro12Arg	missense	Exon 1 of 8	NP_001335971.1
	CCDC74A	NM_138770.4		c.35C>G	p.Pro12Arg	missense	Exon 1 of 8	NP_620125.1	Q96AQ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC74A	ENST00000409856.8	TSL:1 MANE Select	c.35C>G	p.Pro12Arg	missense	Exon 1 of 8	ENSP00000387009.3	Q96AQ1-2
	CCDC74A	ENST00000295171.10	TSL:1	c.35C>G	p.Pro12Arg	missense	Exon 1 of 8	ENSP00000295171.6	Q96AQ1-1
	CCDC74A	ENST00000467992.6	TSL:1	c.35C>G	p.Pro12Arg	missense	Exon 1 of 7	ENSP00000444610.2	F5GZA4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151380 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000228 AC: 3 AN: 1314336 Hom.: 0 Cov.: 30 AF XY: 0.00000156 AC XY: 1 AN XY: 640652

African (AFR) AF: 0.00 AC: 0 AN: 28810

American (AMR) AF: 0.00 AC: 0 AN: 20862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19286

East Asian (EAS) AF: 0.00 AC: 0 AN: 35494

South Asian (SAS) AF: 0.00 AC: 0 AN: 65000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3674

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1042356

Other (OTH) AF: 0.0000185 AC: 1 AN: 54126

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151380 Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2 AN XY: 73918

African (AFR) AF: 0.0000484 AC: 2 AN: 41292

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00 AC: 0 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67662

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.24
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.063
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.067
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.18
MutPred		0.24		Gain of MoRF binding (P = 0.0031)
MVP		0.30
MPC		1.9
ClinPred		0.88	D
GERP RS		2.0
PromoterAI		0.0072	Neutral
Varity_R		0.12
gMVP		0.23
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs767296333; hg19: chr2-132285578;