rs141634296

Variant names:

• chr5-147828022-C-A
• rs141634296
• NM_001379610.1:c.194G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-147828022-C-A
• chr5-147828022-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_001379610.1(SPINK1):​c.194G>T​(p.Arg65Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R65W) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SPINK1 NM_001379610.1 missense, splice_region
• Scores: Splicing: ADA: 0.9968
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.44
• Publications: 21 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, MODERATE, SUPPORTIVE, NO_KNOWN Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 5-147828022-C-A is Benign according to our data. Variant chr5-147828022-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3961102.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	NM_001379610.1	MANE Select	c.194G>T	p.Arg65Leu	missense splice_region	Exon 3 of 4	NP_001366539.1	P00995
	SPINK1	NM_001354966.2		c.194G>T	p.Arg65Leu	missense splice_region	Exon 4 of 5	NP_001341895.1	P00995
	SPINK1	NM_003122.5		c.194G>T	p.Arg65Leu	missense splice_region	Exon 4 of 5	NP_003113.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.194G>T	p.Arg65Leu	missense splice_region	Exon 3 of 4	ENSP00000296695.5	P00995
	SPINK1	ENST00000510027.2	TSL:3	c.194G>T	p.Arg65Leu	missense	Exon 3 of 3	ENSP00000427376.1	D6RIU5
	SPINK1	ENST00000505722.1	TSL:2	n.109G>T		splice_region non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151888 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74182

African (AFR) AF: 0.00 AC: 0 AN: 41362

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 2348

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.4
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.97	T
PhyloP100		-1.4
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.15
Sift	Benign	0.25	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.20
MutPred		0.63		Gain of ubiquitination at K66 (P = 0.0472)
MVP		0.49
MPC		0.020
ClinPred		0.070	T
GERP RS		-3.3
Varity_R		0.33
gMVP		0.71
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.77
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: rs141634296; hg19: chr5-147207585;