chr2-32414937-G-A

Position:

• chr2-32414937-G-A

Variant summary

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

The NM_016252.4(BIRC6):​c.1646G>A​(p.Ser549Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 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: BIRC6 NM_016252.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

Genes affected

BIRC6 (HGNC:13516): (baculoviral IAP repeat containing 6) This gene encodes a protein with a BIR (baculoviral inhibition of apoptosis protein repeat) domain and a UBCc (ubiquitin-conjugating enzyme E2, catalytic) domain. This protein inhibits apoptosis by facilitating the degradation of apoptotic proteins by ubiquitination. [provided by RefSeq, Jul 2008]

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=0.18039268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BIRC6	NM_016252.4	c.1646G>A	p.Ser549Asn	missense_variant	10/74	ENST00000421745.7	NP_057336.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BIRC6	ENST00000421745.7	c.1646G>A	p.Ser549Asn	missense_variant	10/74	1	NM_016252.4	ENSP00000393596	P2
BIRC6	ENST00000700518.1	c.1646G>A	p.Ser549Asn	missense_variant	10/73			ENSP00000515025	A2
BIRC6	ENST00000700519.1	c.1646G>A	p.Ser549Asn	missense_variant	10/74			ENSP00000515026
BIRC6	ENST00000648282.1	c.1484G>A	p.Ser495Asn	missense_variant	10/58			ENSP00000498175

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Dec 27, 2022

The c.1646G>A (p.S549N) alteration is located in exon 10 (coding exon 10) of the BIRC6 gene. This alteration results from a G to A substitution at nucleotide position 1646, causing the serine (S) at amino acid position 549 to be replaced by an asparagine (N). 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	0.099
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	0.040
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.22
Sift	Benign	0.091	T
Sift4G	Uncertain	0.0040	D
Vest4		0.23
MutPred		0.10		Gain of methylation at K548 (P = 0.0894);
MVP		0.63
MPC		0.16
ClinPred		0.51	D
GERP RS		4.2
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

LitVar

Other links and lift over

dbSNP: rs777391340; hg19: chr2-32640005;