NM_001258306.3:c.257A>G

Variant names:

• chr2-131529653-A-G
• rs147307685
• NM_001258306.3:c.257A>G

Variant summary

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

The NM_001258306.3(CCDC74A):​c.257A>G​(p.His86Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,732 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CCDC74A NM_001258306.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08
• Publications: 0 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=0.016404033).

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.257A>G	p.His86Arg	missense	Exon 2 of 8	NP_001245235.1	Q96AQ1-2
	CCDC74A	NM_001349042.2		c.383A>G	p.His128Arg	missense	Exon 2 of 8	NP_001335971.1
	CCDC74A	NM_138770.4		c.257A>G	p.His86Arg	missense	Exon 2 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.257A>G	p.His86Arg	missense	Exon 2 of 8	ENSP00000387009.3	Q96AQ1-2
	CCDC74A	ENST00000295171.10	TSL:1	c.257A>G	p.His86Arg	missense	Exon 2 of 8	ENSP00000295171.6	Q96AQ1-1
	CCDC74A	ENST00000467992.6	TSL:1	c.257A>G	p.His86Arg	missense	Exon 2 of 7	ENSP00000444610.2	F5GZA4

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 251074 AF XY: 0.0000737

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461392 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727030

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

African (AFR) AF: 0.000538 AC: 18 AN: 33434

American (AMR) AF: 0.0000895 AC: 4 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111644

Other (OTH) AF: 0.0000497 AC: 3 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000888178), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74502

African (AFR) AF: 0.000818 AC: 34 AN: 41574

American (AMR) AF: 0.000457 AC: 7 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.33
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.67
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.075
Sift	Benign	0.14	T
Sift4G	Benign	0.23	T
Polyphen		0.014	B
Vest4		0.34
MVP		0.25
MPC		1.5
ClinPred		0.022	T
GERP RS		1.7
PromoterAI		-0.0016	Neutral
Varity_R		0.083
gMVP		0.23
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147307685; hg19: chr2-132287226; COSMIC: COSV54608272;