Genetic Variant NM_017636.4:c.16_18delAAG (chr19-49157879-GAGA-G) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PM4_SupportingBS2

The NM_017636.4(TRPM4):c.16_18delAAG(p.Lys6del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000868 in 1,382,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K6K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

TRPM4
NM_017636.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.82

Publications

0 publications found

Variant links:

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

TRPM4 Gene-Disease associations (from GenCC):

erythrokeratodermia variabilis et progressiva 6
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
progressive familial heart block type IB
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
erythrokeratodermia variabilis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive familial heart block
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

TRPM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_017636.4. Strenght limited to Supporting due to length of the change: 1aa.

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4 link	c.16_18delAAG	p.Lys6del	conservative_inframe_deletion	Exon 1 of 25	ENST00000252826.10	NP_060106.2	Q8TD43-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 link	c.16_18delAAG	p.Lys6del	conservative_inframe_deletion	Exon 1 of 25	1	NM_017636.4	ENSP00000252826.4		Q8TD43-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000868

AC:

AN:

1382782

Hom.:

AF XY:

0.00000879

AC XY:

AN XY:

682348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31552

American (AMR)

AF:

0.00

AC:

AN:

35666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25154

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79146

European-Finnish (FIN)

AF:

0.0000292

AC:

AN:

34278

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5024

European-Non Finnish (NFE)

AF:

0.00000742

AC:

AN:

1078432

Other (OTH)

AF:

0.0000519

AC:

AN:

57792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Progressive familial heart block type IB

Uncertain:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.16_18del, results in the deletion of 1 amino acid(s) of the TRPM4 protein (p.Lys6del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRPM4-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

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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NM_017636.4:c.16_18delAAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over