21-36070131-C-G

Variant names:

• chr21-36070131-C-G
• rs1223191674
• NM_001757.4:c.16C>G

Variant summary

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

The NM_001757.4(CBR1):​c.16C>G​(p.His6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,383,490 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: CBR1 NM_001757.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

Genes affected

CBR1 (HGNC:1548): (carbonyl reductase 1) The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2013]

SETD4 (HGNC:1258): (SET domain containing 4) Enables histone methyltransferase activity (H4-K20 specific). Involved in histone H4-K20 trimethylation. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CBR1-AS1 (HGNC:55777): (CBR1 antisense RNA 1)

ENSG00000289001 (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=0.1352706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBR1	NM_001757.4	c.16C>G	p.His6Asp	missense_variant	Exon 1 of 3	ENST00000290349.11	NP_001748.1
CBR1	NM_001286789.2	c.16C>G	p.His6Asp	missense_variant	Exon 1 of 3		NP_001273718.1
CBR1-AS1	NR_040084.1	n.732G>C		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBR1	ENST00000290349.11	c.16C>G	p.His6Asp	missense_variant	Exon 1 of 3	1	NM_001757.4	ENSP00000290349.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1383490 Hom.: 0 Cov.: 30 AF XY: 0.00000588 AC XY: 4 AN XY: 680360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000184

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16C>G (p.H6D) alteration is located in exon 1 (coding exon 1) of the CBR1 gene. This alteration results from a C to G substitution at nucleotide position 16, causing the histidine (H) at amino acid position 6 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.15	.;T;.;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.0010	.;B;B;.
Vest4		0.21
MutPred		0.53		Gain of catalytic residue at H6 (P = 0.0469);Gain of catalytic residue at H6 (P = 0.0469);Gain of catalytic residue at H6 (P = 0.0469);Gain of catalytic residue at H6 (P = 0.0469);
MVP		0.24
MPC		0.35
ClinPred		0.20	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.35
gMVP		0.65

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: rs1223191674; hg19: chr21-37442429;