chr12-21373419-C-A

Variant names:

• chr12-21373419-C-A
• NM_000415.3:c.68C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000415.3(IAPP):​c.68C>A​(p.Thr23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T23I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: IAPP NM_000415.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.982

Genes affected

IAPP (HGNC:5329): (islet amyloid polypeptide) This gene encodes a member of the calcitonin family of peptide hormones. This hormone is released from pancreatic beta cells following food intake to regulate blood glucose levels and act as a satiation signal. Human patients with type 1 and advanced type 2 diabetes exhibit reduced levels of the encoded hormone in blood and pancreas. This protein also exhibits a bactericidal, antimicrobial activity. [provided by RefSeq, Jul 2016]

SLCO1A2 (HGNC:10956): (solute carrier organic anion transporter family member 1A2) This gene encodes a sodium-independent transporter which mediates cellular uptake of organic ions in the liver. Its substrates include bile acids, bromosulphophthalein, and some steroidal compounds. The protein is a member of the SLC21A family of solute carriers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1468721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IAPP	NM_000415.3	c.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 3	ENST00000240652.8	NP_000406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IAPP	ENST00000240652.8	c.68C>A	p.Thr23Lys	missense_variant	Exon 2 of 3	1	NM_000415.3	ENSP00000240652.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459408 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.53
DEOGEN2	Uncertain	0.49	T;T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.60	.;T;T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.90	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.66	N;N;D;N
REVEL	Benign	0.11
Sift	Benign	0.17	T;T;.;T
Sift4G	Benign	0.20	T;T;D;T
Polyphen		0.45	B;B;.;.
Vest4		0.26
MVP		0.76
MPC		0.12
ClinPred		0.53	D
GERP RS		1.8
Varity_R		0.065
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr12-21526353;