7-142876777-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5BP4BS1_Supporting

The NM_018646.6(TRPV6):c.668T>C(p.Ile223Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

TRPV6
NM_018646.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.05

Publications

8 publications found

Variant links:

Genes affected

TRPV6 (HGNC:14006): (transient receptor potential cation channel subfamily V member 6) This gene encodes a member of a family of multipass membrane proteins that functions as calcium channels. The encoded protein contains N-terminal ankyrin repeats, which are required for channel assembly and regulation. Translation initiation for this protein occurs at a non-AUG start codon that is decoded as methionine. This gene is situated next to a closely related gene for transient receptor potential cation channel subfamily V member 5 (TRPV5). This locus has experienced positive selection in non-African populations, resulting in several non-synonymous codon differences among individuals of different genetic backgrounds. [provided by RefSeq, Feb 2015]

TRPV6 Gene-Disease associations (from GenCC):

hyperparathyroidism, transient neonatal
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P
intestinal hypomagnesemia 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
pancreatitis
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
neonatal severe primary hyperparathyroidism
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TRPV6 links:

ENSG00000224970 (HGNC:):

ENSG00000224970 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP5

Variant 7-142876777-A-G is Pathogenic according to our data. Variant chr7-142876777-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 590766.

BP4

Computational evidence support a benign effect (MetaRNN=0.0972462). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000204 (31/152192) while in subpopulation AMR AF = 0.0015 (23/15304). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018646.6. 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
	TRPV6	NM_018646.6	MANE Select	c.668T>C	p.Ile223Thr	missense	Exon 5 of 15	NP_061116.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPV6	ENST00000359396.9	TSL:1 MANE Select	c.668T>C	p.Ile223Thr	missense	Exon 5 of 15	ENSP00000352358.5
TRPV6	ENST00000436401.1	TSL:4	c.-67-1252T>C		intron	N/A	ENSP00000411100.1
TRPV6	ENST00000474388.1	TSL:2	n.32T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000135

AC:

AN:

251454

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00174

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00219

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112000

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000204

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41514

American (AMR)

AF:

0.00150

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000581

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67998

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000788

Hom.:

Bravo

AF:

0.000423

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperparathyroidism, transient neonatal

Pathogenic:3

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 14, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 21, 2019

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Likely pathogenic for Hyperparathyroidism, transient neonatal, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting; PP3; PS3-Supporting; PP1; PM3.

not provided

Uncertain:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 223 of the TRPV6 protein (p.Ile223Thr). This variant is present in population databases (rs529924080, gnomAD 0.2%). This missense change has been observed in individuals with chronic pancreatitis and/or transient neonatal hyperparathyroidism (PMID: 29861107, 30820485, 31930989, 32383311, 36599151). ClinVar contains an entry for this variant (Variation ID: 590766). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TRPV6 function (PMID: 29861107, 31930989, 32383311). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.083

MetaRNN

Benign

0.097

MetaSVM

Uncertain

-0.27

PhyloP100

9.0

PrimateAI

Uncertain

0.58

REVEL

Uncertain

0.53

Sift4G

Pathogenic

0.0010

Vest4

0.86

MVP

0.65

MPC

1.1

ClinPred

0.16

GERP RS

4.7

Varity_R

0.29

gMVP

0.73

Mutation Taster

=50/50

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over