chr5-147824693-A-G

Variant names:

• chr5-147824693-A-G
• rs373011963
• NM_001379610.1:c.208T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001379610.1(SPINK1):​c.208T>C​(p.Ser70Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. S70T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPINK1 NM_001379610.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• Publications: 0 publications found

Genes affected

SPINK1 (HGNC:11244): (serine peptidase inhibitor Kazal type 1) The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis. [provided by RefSeq, Oct 2008]

SPINK1 Gene-Disease associations (from GenCC):

• hereditary chronic pancreatitis

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• tropical pancreatitis

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16066018).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379610.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	NM_001379610.1	MANE Select	c.208T>C	p.Ser70Pro	missense	Exon 4 of 4	NP_001366539.1
	SPINK1	NM_001354966.2		c.208T>C	p.Ser70Pro	missense	Exon 5 of 5	NP_001341895.1
	SPINK1	NM_003122.5		c.208T>C	p.Ser70Pro	missense	Exon 5 of 5	NP_003113.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.208T>C	p.Ser70Pro	missense	Exon 4 of 4	ENSP00000296695.5
	SPINK1	ENST00000505722.1	TSL:2	n.123T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.69
DANN	Benign	0.60
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00094	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.0040
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.085
Sift	Benign	0.24	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.063
MutPred		0.43		Loss of phosphorylation at S70 (P = 0.0665)
MVP		0.51
MPC		0.020
ClinPred		0.28	T
GERP RS		1.1
Varity_R		0.30
gMVP		0.70
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs373011963; hg19: chr5-147204256;