2-130140277-T-G

Variant names:

• chr2-130140277-T-G
• rs142933831
• NM_001258307.2:c.580A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001258307.2(CCDC74B):​c.580A>C​(p.Met194Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,461,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 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. M194V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CCDC74B NM_001258307.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 0 publications found

Genes affected

CCDC74B (HGNC:25267): (coiled-coil domain containing 74B)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258307.2. 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
	CCDC74B	NM_001258307.2	MANE Select	c.580A>C	p.Met194Leu	missense	Exon 5 of 8	NP_001245236.1	Q96LY2-2
	CCDC74B	NM_207310.4		c.778A>C	p.Met260Leu	missense	Exon 5 of 8	NP_997193.1	Q96LY2-1
	CCDC74B	NR_165309.1		n.863A>C		non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC74B	ENST00000409943.8	TSL:1 MANE Select	c.580A>C	p.Met194Leu	missense	Exon 5 of 8	ENSP00000386294.3	Q96LY2-2
	CCDC74B	ENST00000860854.1		c.790A>C	p.Met264Leu	missense	Exon 5 of 8	ENSP00000530913.1
	CCDC74B	ENST00000944366.1		c.790A>C	p.Met264Leu	missense	Exon 5 of 8	ENSP00000614425.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1461022 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 726802

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111644

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.48
DANN	Benign	0.37
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.016
Sift	Benign	0.97	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.030
MPC		1.3
ClinPred		0.050	T
GERP RS		-4.3
Varity_R		0.21
gMVP		0.055
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142933831; hg19: chr2-130897850;