NM_007272.3:c.514A>G

Variant names:

• chr1-15444626-A-G
• rs34949635
• NM_007272.3:c.514A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007272.3(CTRC):​c.514A>G​(p.Lys172Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,614,088 control chromosomes in the GnomAD database, including 372 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K172K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (194 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (178 hom.)
• Consequence: CTRC NM_007272.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.55
• Publications: 8 publications found

Genes affected

CTRC (HGNC:2523): (chymotrypsin C) This gene encodes a member of the peptidase S1 family. The encoded protein is a serum calcium-decreasing factor that has chymotrypsin-like protease activity. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

CTRC Gene-Disease associations (from GenCC):

• hereditary chronic pancreatitis

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00475654).
• BP6: Variant 1-15444626-A-G is Benign according to our data. Variant chr1-15444626-A-G is described in ClinVar as Benign. ClinVar VariationId is 260158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007272.3. 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
	CTRC	NM_007272.3	MANE Select	c.514A>G	p.Lys172Glu	missense	Exon 6 of 8	NP_009203.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRC	ENST00000375949.5	TSL:1 MANE Select	c.514A>G	p.Lys172Glu	missense	Exon 6 of 8	ENSP00000365116.4
	CTRC	ENST00000375943.6	TSL:1	c.*94-971A>G		intron	N/A	ENSP00000365110.2
	CTRC	ENST00000483406.1	TSL:5	n.404-971A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3961 AN: 152090 Hom.: 193 Cov.: 32

Gnomad AFR AF: 0.0897

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00720 AC: 1811 AN: 251392 AF XY: 0.00557

Gnomad AFR exome AF: 0.0918

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00297 AC: 4345 AN: 1461880 Hom.: 178 Cov.: 32 AF XY: 0.00280 AC XY: 2033 AN XY: 727240

African (AFR) AF: 0.0943 AC: 3158 AN: 33476

American (AMR) AF: 0.00369 AC: 165 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00470 AC: 405 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1112004

Other (OTH) AF: 0.00646 AC: 390 AN: 60396

GnomAD4 genome AF: 0.0261 AC: 3974 AN: 152208 Hom.: 194 Cov.: 32 AF XY: 0.0251 AC XY: 1866 AN XY: 74418

African (AFR) AF: 0.0897 AC: 3725 AN: 41520

American (AMR) AF: 0.0109 AC: 166 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 68000

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.00562 Hom.: 66

Bravo AF: 0.0298

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0883 AC: 389

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00886 AC: 1076

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary pancreatitis (4)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.59	N
PhyloP100		1.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.70
MPC		0.26
ClinPred		0.00094	T
GERP RS		3.2
Varity_R		0.13
gMVP		0.76
Mutation Taster		=100/0	polymorphism (auto)

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: rs34949635; hg19: chr1-15771121;