2-130141194-T-G

Position:

• chr2-130141194-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001258307.2(CCDC74B):​c.449A>C​(p.Lys150Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 29)
• Consequence: CCDC74B NM_001258307.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0930

Genes affected

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

CCDC74B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21341074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC74B	NM_001258307.2	c.449A>C	p.Lys150Thr	missense_variant	4/8	ENST00000409943.8	NP_001245236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC74B	ENST00000409943.8	c.449A>C	p.Lys150Thr	missense_variant	4/8	1	NM_001258307.2	ENSP00000386294.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151682 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151682 Hom.: 0 Cov.: 29 AF XY: 0.0000270 AC XY: 2 AN XY: 74058

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.647A>C (p.K216T) alteration is located in exon 4 (coding exon 4) of the CCDC74B gene. This alteration results from a A to C substitution at nucleotide position 647, causing the lysine (K) at amino acid position 216 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.6	.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.2	N;N;.;N
REVEL	Benign	0.095
Sift	Benign	0.099	T;D;.;D
Sift4G	Uncertain	0.048	D;T;D;D
Polyphen		0.99	D;D;.;.
Vest4		0.38
MVP		0.65
MPC		2.8
ClinPred		0.40	T
GERP RS		0.66
Varity_R		0.17
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1685597793; hg19: chr2-130898767;