2-32414845-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016252.4(BIRC6):c.1554A>G(p.Lys518=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,613,924 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (5 hom.)
• Consequence: BIRC6 NM_016252.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.17

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-32414845-A-G is Benign according to our data. Variant chr2-32414845-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 719772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BS2: High AC in GnomAd at 236 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BIRC6	NM_016252.4	c.1554A>G	p.Lys518=	synonymous_variant	10/74	ENST00000421745.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BIRC6	ENST00000421745.7	c.1554A>G	p.Lys518=	synonymous_variant	10/74	1	NM_016252.4	P2
BIRC6	ENST00000700518.1	c.1554A>G	p.Lys518=	synonymous_variant	10/73			A2
BIRC6	ENST00000700519.1	c.1554A>G	p.Lys518=	synonymous_variant	10/74
BIRC6	ENST00000648282.1	c.1392A>G	p.Lys464=	synonymous_variant	10/58

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00187 AC: 470 AN: 251118 Hom.: 0 AF XY: 0.00200 AC XY: 272 AN XY: 135712

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00249 AC: 3639 AN: 1461654 Hom.: 5 Cov.: 31 AF XY: 0.00250 AC XY: 1817 AN XY: 727102

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00296

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00155 AC: 236 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74458

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00263

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00193 Hom.: 0

Bravo AF: 0.00171

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	BIRC6: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jun 08, 2018	- -

BIRC6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	4.6
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs144006143; hg19: chr2-32639913; COSMIC: COSV101429533;