2-131530647-G-C

Variant names:

• chr2-131530647-G-C
• rs148324548
• ENST00000295171.10:c.364G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001349042.2(CCDC74A):​c.490G>C​(p.Gly164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,612,274 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: CCDC74A NM_001349042.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 7 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061077774).

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.296-130G>C		intron	N/A	NP_001245235.1	Q96AQ1-2
	CCDC74A	NM_001349042.2		c.490G>C	p.Gly164Arg	missense	Exon 3 of 8	NP_001335971.1
	CCDC74A	NM_138770.4		c.364G>C	p.Gly122Arg	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.364G>C	p.Gly122Arg	missense	Exon 3 of 8	ENSP00000295171.6	Q96AQ1-1
	CCDC74A	ENST00000467992.6	TSL:1	c.364G>C	p.Gly122Arg	missense	Exon 3 of 7	ENSP00000444610.2	F5GZA4
	CCDC74A	ENST00000409856.8	TSL:1 MANE Select	c.296-130G>C		intron	N/A	ENSP00000387009.3	Q96AQ1-2

Frequencies

GnomAD3 genomes AF: 0.000995 AC: 151 AN: 151690 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00991

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00118 AC: 288 AN: 243486 AF XY: 0.00104

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000326

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00767

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000508

GnomAD4 exome AF: 0.00121 AC: 1770 AN: 1460468 Hom.: 1 Cov.: 38 AF XY: 0.00114 AC XY: 828 AN XY: 726524

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

African (AFR) AF: 0.000179 AC: 6 AN: 33468

American (AMR) AF: 0.000358 AC: 16 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26122

East Asian (EAS) AF: 0.00567 AC: 225 AN: 39648

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86216

European-Finnish (FIN) AF: 0.000510 AC: 27 AN: 52922

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00127 AC: 1408 AN: 1111358

Other (OTH) AF: 0.00108 AC: 65 AN: 60336

⚠️ 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: 0.000995 AC: 151 AN: 151806 Hom.: 0 Cov.: 29 AF XY: 0.00119 AC XY: 88 AN XY: 74208

African (AFR) AF: 0.000315 AC: 13 AN: 41284

American (AMR) AF: 0.000590 AC: 9 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00994 AC: 51 AN: 5132

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 67970

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000475 Hom.: 0

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.00130 AC: 11

ExAC AF: 0.00126 AC: 152

EpiCase AF: 0.00142

EpiControl AF: 0.000713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.91
DANN	Benign	0.77
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.3
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.038
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.80	T
Polyphen		1.0	D
Vest4		0.097
MutPred		0.41		Gain of sheet (P = 0.0085)
MVP		0.33
MPC		1.8
ClinPred		0.031	T
GERP RS		-2.8
Varity_R		0.089
gMVP		0.12
Mutation Taster		=95/5	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: rs148324548; hg19: chr2-132288220;