2-131530663-C-T

Variant names:

• chr2-131530663-C-T
• rs10190564
• ENST00000295171.10:c.380C>T

Variant summary

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

The NM_001349042.2(CCDC74A):​c.506C>T​(p.Pro169Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 151,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CCDC74A NM_001349042.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.01
• Publications: 2 publications found

Genes affected

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

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=0.0375551).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349042.2. 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.296-114C>T		intron	N/A	NP_001245235.1	Q96AQ1-2
	CCDC74A	NM_001349042.2		c.506C>T	p.Pro169Leu	missense	Exon 3 of 8	NP_001335971.1
	CCDC74A	NM_138770.4		c.380C>T	p.Pro127Leu	missense	Exon 3 of 8	NP_620125.1	Q96AQ1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC74A	ENST00000295171.10	TSL:1	c.380C>T	p.Pro127Leu	missense	Exon 3 of 8	ENSP00000295171.6	Q96AQ1-1
	CCDC74A	ENST00000467992.6	TSL:1	c.380C>T	p.Pro127Leu	missense	Exon 3 of 7	ENSP00000444610.2	F5GZA4
	CCDC74A	ENST00000409856.8	TSL:1 MANE Select	c.296-114C>T		intron	N/A	ENSP00000387009.3	Q96AQ1-2

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151476 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000769 AC: 19 AN: 246978 AF XY: 0.0000819

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000167

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000705 AC: 103 AN: 1460634 Hom.: 0 Cov.: 38 AF XY: 0.0000661 AC XY: 48 AN XY: 726650

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

African (AFR) AF: 0.0000598 AC: 2 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86226

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000828 AC: 92 AN: 1111444

Other (OTH) AF: 0.0000331 AC: 2 AN: 60348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151476 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73958

African (AFR) AF: 0.0000732 AC: 3 AN: 40978

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000194 Hom.: 0

ExAC AF: 0.0000989 AC: 12

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	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.0
DANN	Benign	0.82
DEOGEN2	Benign	0.00051	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-5.0
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.020
Sift	Benign	0.41	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.30		Gain of sheet (P = 0.0028)
MVP		0.048
MPC		1.2
ClinPred		0.012	T
GERP RS		-3.0
Varity_R		0.021
gMVP		0.10
Mutation Taster		=88/12	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: rs10190564; hg19: chr2-132288236;