chr19-49168723-G-A

Variant names:

• chr19-49168723-G-A
• rs111930830
• NM_017636.4:c.783G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_017636.4(TRPM4):​c.783G>A​(p.Lys261Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,591,836 control chromosomes in the GnomAD database, including 376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (49 hom., cov: 30)
  • Exomes 𝑓: 0.017 (327 hom.)
• Consequence: TRPM4 NM_017636.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.20
• Publications: 2 publications found

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: Labcorp Genetics (formerly Invitae), G2P, 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-49168723-G-A is Benign according to our data. Variant chr19-49168723-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0186 (2826/152094) while in subpopulation SAS AF = 0.036 (173/4806). AF 95% confidence interval is 0.0316. There are 49 homozygotes in GnomAd4. There are 1449 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2826 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017636.4. 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
	TRPM4	NM_017636.4	MANE Select	c.783G>A	p.Lys261Lys	synonymous	Exon 6 of 25	NP_060106.2
	TRPM4	NM_001321281.2		c.438G>A	p.Lys146Lys	synonymous	Exon 4 of 23	NP_001308210.1
	TRPM4	NM_001195227.2		c.783G>A	p.Lys261Lys	synonymous	Exon 6 of 24	NP_001182156.1	Q8TD43-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM4	ENST00000252826.10	TSL:1 MANE Select	c.783G>A	p.Lys261Lys	synonymous	Exon 6 of 25	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.783G>A	p.Lys261Lys	synonymous	Exon 6 of 24	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.*193G>A		non_coding_transcript_exon	Exon 4 of 23	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2824 AN: 151976 Hom.: 49 Cov.: 30

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0216 AC: 4506 AN: 208910 AF XY: 0.0229

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.00672

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.000192

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0170 AC: 24405 AN: 1439742 Hom.: 327 Cov.: 33 AF XY: 0.0179 AC XY: 12755 AN XY: 714266

African (AFR) AF: 0.0139 AC: 462 AN: 33150

American (AMR) AF: 0.00694 AC: 285 AN: 41046

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 766 AN: 25614

East Asian (EAS) AF: 0.0000774 AC: 3 AN: 38738

South Asian (SAS) AF: 0.0351 AC: 2923 AN: 83324

European-Finnish (FIN) AF: 0.0345 AC: 1738 AN: 50414

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5742

European-Non Finnish (NFE) AF: 0.0156 AC: 17174 AN: 1102056

Other (OTH) AF: 0.0161 AC: 963 AN: 59658

GnomAD4 genome AF: 0.0186 AC: 2826 AN: 152094 Hom.: 49 Cov.: 30 AF XY: 0.0195 AC XY: 1449 AN XY: 74348

African (AFR) AF: 0.0144 AC: 599 AN: 41500

American (AMR) AF: 0.00701 AC: 107 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.0360 AC: 173 AN: 4806

European-Finnish (FIN) AF: 0.0356 AC: 377 AN: 10584

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0208 AC: 1413 AN: 67984

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0217 Hom.: 40

Bravo AF: 0.0149

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Progressive familial heart block type IB (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	TRPM4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.36
PhyloP100		1.2
Mutation Taster		=241/59	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: rs111930830; hg19: chr19-49671980; COSMIC: COSV53266352; COSMIC: COSV53266352;