rs111966833

Variant names:

• chr5-147828053-G-A
• rs111966833
• NM_001379610.1:c.163C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-147828053-G-A
• chr5-147828053-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379610.1(SPINK1):​c.163C>T​(p.Pro55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,613,290 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P55P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (49 hom.)
• Consequence: SPINK1 NM_001379610.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -7.04
• Publications: 60 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010206819).
• BP6: Variant 5-147828053-G-A is Benign according to our data. Variant chr5-147828053-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00373 (567/152180) while in subpopulation NFE AF = 0.00609 (414/67990). AF 95% confidence interval is 0.0056. There are 3 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 567 AD,Unknown gene.

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.163C>T	p.Pro55Ser	missense	Exon 3 of 4	NP_001366539.1	P00995
	SPINK1	NM_001354966.2		c.163C>T	p.Pro55Ser	missense	Exon 4 of 5	NP_001341895.1	P00995
	SPINK1	NM_003122.5		c.163C>T	p.Pro55Ser	missense	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.163C>T	p.Pro55Ser	missense	Exon 3 of 4	ENSP00000296695.5	P00995
	SPINK1	ENST00000510027.2	TSL:3	c.163C>T	p.Pro55Ser	missense	Exon 3 of 3	ENSP00000427376.1	D6RIU5
	SPINK1	ENST00000505722.1	TSL:2	n.78C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 568 AN: 152062 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00448 AC: 1123 AN: 250482 AF XY: 0.00493

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.000895

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00651

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00623 AC: 9101 AN: 1461110 Hom.: 49 Cov.: 30 AF XY: 0.00613 AC XY: 4459 AN XY: 726864

African (AFR) AF: 0.000896 AC: 30 AN: 33468

American (AMR) AF: 0.00239 AC: 107 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26114

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39584

South Asian (SAS) AF: 0.00675 AC: 582 AN: 86232

European-Finnish (FIN) AF: 0.00299 AC: 159 AN: 53178

Middle Eastern (MID) AF: 0.00608 AC: 35 AN: 5754

European-Non Finnish (NFE) AF: 0.00696 AC: 7739 AN: 1111706

Other (OTH) AF: 0.00699 AC: 422 AN: 60358

GnomAD4 genome AF: 0.00373 AC: 567 AN: 152180 Hom.: 3 Cov.: 32 AF XY: 0.00370 AC XY: 275 AN XY: 74402

African (AFR) AF: 0.00104 AC: 43 AN: 41532

American (AMR) AF: 0.00307 AC: 47 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4814

European-Finnish (FIN) AF: 0.00236 AC: 25 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00609 AC: 414 AN: 67990

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00497 Hom.: 3

Bravo AF: 0.00397

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00446 AC: 541

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00753

EpiControl AF: 0.00611

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Hereditary pancreatitis (8)
-	-	6	not provided (6)
-	-	1	not specified (1)
-	-	1	SPINK1-related disorder (1)
-	-	1	Tropical pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0010
DANN	Benign	0.14
DEOGEN2	Benign	0.12	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.99	T
PhyloP100		-7.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.12
Sift	Benign	0.75	T
Sift4G	Benign	0.70	T
Polyphen		0.012	B
Vest4		0.060
MVP		0.15
MPC		0.019
ClinPred		0.0075	T
GERP RS		-9.8
Varity_R		0.081
gMVP		0.73
Mutation Taster		=97/3	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: rs111966833; hg19: chr5-147207616; COSMIC: COSV57025043;