4-155863689-T-C

Variant summary

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

The NM_017419.3(ASIC5):c.106A>G(p.Lys36Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 12/21 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: ASIC5 NM_017419.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

Genes affected

ASIC5 (HGNC:17537): (acid sensing ion channel subunit family member 5) This gene belongs to the amiloride-sensitive Na+ channel and degenerin (NaC/DEG) family, members of which have been identified in many animal species ranging from the nematode to human. The amiloride-sensitive Na(+) channel encoded by this gene is primarily expressed in the small intestine, however, its exact function is not known. [provided by RefSeq, Jul 2008]

LOC105377507 (HGNC:):

TDO2 (HGNC:11708): (tryptophan 2,3-dioxygenase) This gene encodes a heme enzyme that plays a critical role in tryptophan metabolism by catalyzing the first and rate-limiting step of the kynurenine pathway. Increased activity of the encoded protein and subsequent kynurenine production may also play a role in cancer through the suppression of antitumor immune responses, and single nucleotide polymorphisms in this gene may be associated with autism. [provided by RefSeq, Feb 2012]

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
ASIC5	NM_017419.3	c.106A>G	p.Lys36Glu	missense_variant	2/10	ENST00000537611.3
LOC105377507	XR_001741901.2	n.211+4791T>C		intron_variant, non_coding_transcript_variant
ASIC5	XM_017008291.2	c.106A>G	p.Lys36Glu	missense_variant	2/9
LOC105377507	XR_939389.3	n.5002T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASIC5	ENST00000537611.3	c.106A>G	p.Lys36Glu	missense_variant	2/10	1	NM_017419.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Feb 07, 2023

The c.106A>G (p.K36E) alteration is located in exon 2 (coding exon 2) of the ASIC5 gene. This alteration results from a A to G substitution at nucleotide position 106, causing the lysine (K) at amino acid position 36 to be replaced by a glutamic acid (E). 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	-0.0065	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.57	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.18
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.014	D
Polyphen		0.23	B
Vest4		0.59
MutPred		0.35		Loss of methylation at K36 (P = 0.0015);
MVP		0.40
MPC		0.019
ClinPred		0.59	D
GERP RS		3.1
Varity_R		0.11
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-156784841;