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GeneBe

2-233942727-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_024080.5(TRPM8):c.678C>G(p.Leu226=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,156 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0052 ( 10 hom., cov: 31)
Exomes 𝑓: 0.00075 ( 11 hom. )

Consequence

TRPM8
NM_024080.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.39
Variant links:
Genes affected
TRPM8 (HGNC:17961): (transient receptor potential cation channel subfamily M member 8) Predicted to enable ligand-gated calcium channel activity. Predicted to be involved in calcium ion transmembrane transport and positive regulation of cold-induced thermogenesis. Predicted to act upstream of or within several processes, including cellular calcium ion homeostasis; response to cold; and thermoception. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 2-233942727-C-G is Benign according to our data. Variant chr2-233942727-C-G is described in ClinVar as [Benign]. Clinvar id is 769595.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.39 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00521 (793/152302) while in subpopulation AFR AF= 0.0177 (734/41562). AF 95% confidence interval is 0.0166. There are 10 homozygotes in gnomad4. There are 375 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRPM8NM_024080.5 linkuse as main transcriptc.678C>G p.Leu226= synonymous_variant 6/26 ENST00000324695.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRPM8ENST00000324695.9 linkuse as main transcriptc.678C>G p.Leu226= synonymous_variant 6/261 NM_024080.5 P1Q7Z2W7-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00518
AC:
789
AN:
152184
Hom.:
9
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0176
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.00430
GnomAD3 exomes
AF:
0.00146
AC:
368
AN:
251480
Hom.:
5
AF XY:
0.00113
AC XY:
153
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0165
Gnomad AMR exome
AF:
0.00142
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000343
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.000746
AC:
1090
AN:
1461854
Hom.:
11
Cov.:
31
AF XY:
0.000672
AC XY:
489
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0184
Gnomad4 AMR exome
AF:
0.00132
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000208
Gnomad4 OTH exome
AF:
0.00237
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00521
AC:
793
AN:
152302
Hom.:
10
Cov.:
31
AF XY:
0.00504
AC XY:
375
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0177
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.00425
Alfa
AF:
0.000414
Hom.:
0
Bravo
AF:
0.00586
Asia WGS
AF:
0.00346
AC:
12
AN:
3478
EpiCase
AF:
0.000273
EpiControl
AF:
0.000237

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.46
Cadd
Benign
7.9
Dann
Benign
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28901630; hg19: chr2-234851371; API