2-131530663-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001349042.2(CCDC74A):​c.506C>G​(p.Pro169Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,611,848 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P169L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (61 hom., cov: 29)
  • Exomes 𝑓: 0.0024 (17 hom.)
• Consequence: CCDC74A NM_001349042.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.01
• Publications: 2 publications found

Genes affected

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024795234).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.08 is higher than 0.05.

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>G		intron	N/A	NP_001245235.1	Q96AQ1-2
	CCDC74A	NM_001349042.2		c.506C>G	p.Pro169Arg	missense	Exon 3 of 8	NP_001335971.1
	CCDC74A	NM_138770.4		c.380C>G	p.Pro127Arg	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>G	p.Pro127Arg	missense	Exon 3 of 8	ENSP00000295171.6	Q96AQ1-1
	CCDC74A	ENST00000467992.6	TSL:1	c.380C>G	p.Pro127Arg	missense	Exon 3 of 7	ENSP00000444610.2	F5GZA4
	CCDC74A	ENST00000409856.8	TSL:1 MANE Select	c.296-114C>G		intron	N/A	ENSP00000387009.3	Q96AQ1-2

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3546 AN: 151320 Hom.: 58 Cov.: 29

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00355

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00554 AC: 1369 AN: 246978 AF XY: 0.00404

Gnomad AFR exome AF: 0.0760

Gnomad AMR exome AF: 0.00311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00300

GnomAD4 exome AF: 0.00236 AC: 3445 AN: 1460412 Hom.: 17 Cov.: 38 AF XY: 0.00211 AC XY: 1534 AN XY: 726546

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

African (AFR) AF: 0.0810 AC: 2673 AN: 32992

American (AMR) AF: 0.00387 AC: 173 AN: 44686

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00231 AC: 199 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5726

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111774

Other (OTH) AF: 0.00556 AC: 335 AN: 60306

⚠️ 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: 0.0235 AC: 3559 AN: 151436 Hom.: 61 Cov.: 29 AF XY: 0.0229 AC XY: 1697 AN XY: 74014

African (AFR) AF: 0.0823 AC: 3371 AN: 40944

American (AMR) AF: 0.00788 AC: 120 AN: 15226

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00355 AC: 17 AN: 4786

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67974

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.00116 Hom.: 0

ExAC AF: 0.00781 AC: 948

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.28
DANN	Benign	0.70
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-5.0
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.013
Sift	Benign	0.092	T
Sift4G	Benign	0.52	T
Polyphen		0.0080	B
Vest4		0.051
MVP		0.040
MPC		1.3
ClinPred		0.0037	T
GERP RS		-3.0
Varity_R		0.045
gMVP		0.081
Mutation Taster		=94/6	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; COSMIC: COSV106096639; COSMIC: COSV106096639;