5-151117174-G-A

Variant summary

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

The NM_001155.5(ANXA6):c.1525C>T(p.Arg509Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000457 in 1,589,874 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R509H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: ANXA6 NM_001155.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

Genes affected

ANXA6 (HGNC:544): (annexin A6) Annexin VI belongs to a family of calcium-dependent membrane and phospholipid binding proteins. Several members of the annexin family have been implicated in membrane-related events along exocytotic and endocytotic pathways. The annexin VI gene is approximately 60 kbp long and contains 26 exons. It encodes a protein of about 68 kDa that consists of eight 68-amino acid repeats separated by linking sequences of variable lengths. It is highly similar to human annexins I and II sequences, each of which contain four such repeats. Annexin VI has been implicated in mediating the endosome aggregation and vesicle fusion in secreting epithelia during exocytosis. Alternatively spliced transcript variants have been described. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANXA6	NM_001155.5	c.1525C>T	p.Arg509Cys	missense_variant	20/26	ENST00000354546.10
ANXA6	NM_001363114.2	c.1525C>T	p.Arg509Cys	missense_variant	20/25
ANXA6	NM_001193544.2	c.1429C>T	p.Arg477Cys	missense_variant	19/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANXA6	ENST00000354546.10	c.1525C>T	p.Arg509Cys	missense_variant	20/26	1	NM_001155.5	P4

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000296 AC: 69 AN: 233270 Hom.: 0 AF XY: 0.000331 AC XY: 42 AN XY: 126984

Gnomad AFR exome AF: 0.0000698

Gnomad AMR exome AF: 0.000222

Gnomad ASJ exome AF: 0.00116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000944

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000467 AC: 672 AN: 1437664 Hom.: 0 Cov.: 31 AF XY: 0.000452 AC XY: 323 AN XY: 714442

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.0000266

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.000547

Gnomad4 OTH exome AF: 0.000439

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74402

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000578 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.000248 AC: 30

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

Jul 13, 2022

The c.1525C>T (p.R509C) alteration is located in exon 20 (coding exon 19) of the ANXA6 gene. This alteration results from a C to T substitution at nucleotide position 1525, causing the arginine (R) at amino acid position 509 to be replaced by a cysteine (C). 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	Pathogenic	0.84
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;.;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	4.2	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D;D;D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.063	T;T;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.89
MVP		0.66
MPC		0.49
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.49
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200918889; hg19: chr5-150496735; COSMIC: COSV62907118; COSMIC: COSV62907118;