8-87237048-T-C

Variant summary

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

The NM_173538.3(CNBD1):c.707T>C(p.Ile236Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CNBD1 NM_173538.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.125

Genes affected

CNBD1 (HGNC:26663): (cyclic nucleotide binding domain containing 1)

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=0.086707234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CNBD1	NM_173538.3	c.707T>C	p.Ile236Thr	missense_variant	6/11	ENST00000518476.6
CNBD1	XM_017013149.2	c.707T>C	p.Ile236Thr	missense_variant	6/11
CNBD1	XM_024447082.2	c.707T>C	p.Ile236Thr	missense_variant	6/7
CNBD1	XM_047421411.1	c.542T>C	p.Ile181Thr	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CNBD1	ENST00000518476.6	c.707T>C	p.Ile236Thr	missense_variant	6/11	1	NM_173538.3
CNBD1	ENST00000523299.6	c.707T>C	p.Ile236Thr	missense_variant	6/13	3		P1
CNBD1	ENST00000522105.1	n.221T>C		non_coding_transcript_exon_variant	2/2	3
CNBD1	ENST00000522427.1	n.450T>C		non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 23, 2024

The c.707T>C (p.I236T) alteration is located in exon 6 (coding exon 6) of the CNBD1 gene. This alteration results from a T to C substitution at nucleotide position 707, causing the isoleucine (I) at amino acid position 236 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	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	1.7
Dann	Benign	0.72
DEOGEN2	Benign	0.0018	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.72	N;.
REVEL	Benign	0.0070
Sift	Benign	0.034	D;.
Sift4G	Uncertain	0.031	D;D
Polyphen		0.12	B;.
Vest4		0.23
MutPred		0.41		Loss of stability (P = 0.0129);.;
MVP		0.030
MPC		0.0043
ClinPred		0.076	T
GERP RS		-0.96
Varity_R		0.080
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs1318250472; hg19: chr8-88249276;