17-8369519-C-G

Variant names:

• chr17-8369519-C-G
• NM_001304947.3:c.848G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001304947.3(KRBA2):​c.848G>C​(p.Ser283Thr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S283N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRBA2 NM_001304947.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.292

Genes affected

KRBA2 (HGNC:26989): (KRAB-A domain containing 2) Predicted to enable nucleic acid binding activity. Predicted to be involved in DNA integration and regulation of transcription, DNA-templated. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000263809 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067406446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRBA2	NM_001304947.3	c.848G>C	p.Ser283Thr	missense_variant	Exon 2 of 2	ENST00000396267.3	NP_001291876.1
KRBA2	NM_213597.3	c.1094G>C	p.Ser365Thr	missense_variant	Exon 2 of 2		NP_998762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRBA2	ENST00000396267.3	c.848G>C	p.Ser283Thr	missense_variant	Exon 2 of 2	2	NM_001304947.3	ENSP00000379565.3
ENSG00000263809	ENST00000582471.1	n.*1831G>C		non_coding_transcript_exon_variant	Exon 6 of 6	5		ENSP00000463847.1
ENSG00000263809	ENST00000582471.1	n.*1831G>C		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000463847.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1094G>C (p.S365T) alteration is located in exon 2 (coding exon 2) of the KRBA2 gene. This alteration results from a G to C substitution at nucleotide position 1094, causing the serine (S) at amino acid position 365 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	0.094
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.5
DANN	Benign	0.42
DEOGEN2	Benign	0.024	.;T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.52	.;T;T;.;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;M;M;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.79	.;N;N;.;.
REVEL	Benign	0.069
Sift	Benign	0.21	.;T;T;.;.
Sift4G	Benign	0.48	.;T;T;.;.
Polyphen		0.33	.;.;B;B;.
Vest4		0.28, 0.27
MutPred		0.32		.;.;Loss of disorder (P = 0.0659);Loss of disorder (P = 0.0659);.;
MVP		0.13
MPC		0.14
ClinPred		0.14	T
GERP RS		-5.5
Varity_R		0.057
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-8272837;