chr17-81103530-C-T

Variant names:

• chr17-81103530-C-T
• rs369167632
• NM_001144888.2:c.671C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001385157.1(BAIAP2):​c.-59C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000333 in 1,589,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: BAIAP2 NM_001385157.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

Genes affected

BAIAP2 (HGNC:947): (BAR/IMD domain containing adaptor protein 2) The protein encoded by this gene has been identified as a brain-specific angiogenesis inhibitor (BAI1)-binding protein. This adaptor protein links membrane bound G-proteins to cytoplasmic effector proteins. This protein functions as an insulin receptor tyrosine kinase substrate and suggests a role for insulin in the central nervous system. It also associates with a downstream effector of Rho small G proteins, which is associated with the formation of stress fibers and cytokinesis. This protein is involved in lamellipodia and filopodia formation in motile cells and may affect neuronal growth-cone guidance. This protein has also been identified as interacting with the dentatorubral-pallidoluysian atrophy gene, which is associated with an autosomal dominant neurodegenerative disease. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAIAP2	NM_001144888.2	c.671C>T	p.Pro224Leu	missense_variant	Exon 8 of 14	ENST00000428708.7	NP_001138360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAIAP2	ENST00000428708.7	c.671C>T	p.Pro224Leu	missense_variant	Exon 8 of 14	1	NM_001144888.2	ENSP00000401022.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000623 AC: 13 AN: 208712 Hom.: 0 AF XY: 0.0000690 AC XY: 8 AN XY: 115896

Gnomad AFR exome AF: 0.0000805

Gnomad AMR exome AF: 0.0000616

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000702

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000751

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.0000327 AC: 47 AN: 1437266 Hom.: 0 Cov.: 34 AF XY: 0.0000336 AC XY: 24 AN XY: 714682

Gnomad4 AFR exome AF: 0.0000603

Gnomad4 AMR exome AF: 0.0000463

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000828

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000298

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152240 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.0000584 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671C>T (p.P224L) alteration is located in exon 8 (coding exon 8) of the BAIAP2 gene. This alteration results from a C to T substitution at nucleotide position 671, causing the proline (P) at amino acid position 224 to be replaced by a leucine (L). 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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	.;.;.;.;.;D;T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.1	M;M;M;.;M;M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.4	D;D;.;.;D;D;.;.;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;.;.;D;D;.;.;D
Sift4G	Uncertain	0.0020	D;T;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;D;.;.;D
Vest4		0.81
MVP		0.90
MPC		1.8
ClinPred		0.85	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.90

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: rs369167632; hg19: chr17-79077330;