2-131528004-C-T

Variant names:

• chr2-131528004-C-T
• rs759189333
• NM_001258306.3:c.34C>T

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.34C>T​(p.Pro12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (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: -0.122
• 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=0.18138337).

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.34C>T	p.Pro12Ser	missense	Exon 1 of 8	NP_001245235.1	Q96AQ1-2
	CCDC74A	NM_001349042.2		c.34C>T	p.Pro12Ser	missense	Exon 1 of 8	NP_001335971.1
	CCDC74A	NM_138770.4		c.34C>T	p.Pro12Ser	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.34C>T	p.Pro12Ser	missense	Exon 1 of 8	ENSP00000387009.3	Q96AQ1-2
	CCDC74A	ENST00000295171.10	TSL:1	c.34C>T	p.Pro12Ser	missense	Exon 1 of 8	ENSP00000295171.6	Q96AQ1-1
	CCDC74A	ENST00000467992.6	TSL:1	c.34C>T	p.Pro12Ser	missense	Exon 1 of 7	ENSP00000444610.2	F5GZA4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000229 AC: 3 AN: 1310084 Hom.: 0 Cov.: 30 AF XY: 0.00000157 AC XY: 1 AN XY: 638408

African (AFR) AF: 0.00 AC: 0 AN: 28700

American (AMR) AF: 0.00 AC: 0 AN: 20662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19196

East Asian (EAS) AF: 0.00 AC: 0 AN: 35366

South Asian (SAS) AF: 0.00 AC: 0 AN: 64752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3640

European-Non Finnish (NFE) AF: 0.00000289 AC: 3 AN: 1039160

Other (OTH) AF: 0.00 AC: 0 AN: 54008

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000101 AC: 1

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	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.12
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.17
MutPred		0.28		Gain of phosphorylation at P12 (P = 0.0016)
MVP		0.21
MPC		1.3
ClinPred		0.50	T
GERP RS		2.0
PromoterAI		-0.037	Neutral
Varity_R		0.11
gMVP		0.24
Mutation Taster		=95/5	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: rs759189333; hg19: chr2-132285577;