2-32414970-A-C

Position:

• chr2-32414970-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_016252.4(BIRC6):​c.1679A>C​(p.His560Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00342 in 1,614,004 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (12 hom.)
• Consequence: BIRC6 NM_016252.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.93

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053548515).
• BP6: Variant 2-32414970-A-C is Benign according to our data. Variant chr2-32414970-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 717018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 376 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BIRC6	NM_016252.4	c.1679A>C	p.His560Pro	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.1679A>C	p.His560Pro	missense_variant	10/74	1	NM_016252.4	ENSP00000393596	P2
BIRC6	ENST00000700518.1	c.1679A>C	p.His560Pro	missense_variant	10/73			ENSP00000515025	A2
BIRC6	ENST00000700519.1	c.1679A>C	p.His560Pro	missense_variant	10/74			ENSP00000515026
BIRC6	ENST00000648282.1	c.1517A>C	p.His506Pro	missense_variant	10/58			ENSP00000498175

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152250 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00292 AC: 732 AN: 250976 Hom.: 3 AF XY: 0.00279 AC XY: 378 AN XY: 135664

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00409

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00352 AC: 5141 AN: 1461636 Hom.: 12 Cov.: 31 AF XY: 0.00342 AC XY: 2488 AN XY: 727096

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00232

Gnomad4 NFE exome AF: 0.00385

Gnomad4 OTH exome AF: 0.00379

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152368 Hom.: 3 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74504

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00382 Hom.: 5

Bravo AF: 0.00263

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00299 AC: 363

EpiCase AF: 0.00360

EpiControl AF: 0.00332

ClinVar

Significance: 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2018	- -

BIRC6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as 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
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.95
Eigen	Benign	-0.15
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.33
Sift	Benign	0.040	D
Sift4G	Uncertain	0.013	D
Vest4		0.49
MVP		0.71
MPC		0.27
ClinPred		0.038	T
GERP RS		3.8
gMVP		0.53

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: rs150426823; hg19: chr2-32640038;