19-49168250-G-A

Variant names:

• chr19-49168250-G-A
• rs78444754
• NM_017636.4:c.449-10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017636.4(TRPM4):​c.449-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,614,016 control chromosomes in the GnomAD database, including 574 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (25 hom., cov: 30)
  • Exomes 𝑓: 0.025 (549 hom.)
• Consequence: TRPM4 NM_017636.4 intron
• Scores: Splicing: ADA: 0.001161
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.410
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-49168250-G-A is Benign according to our data. Variant chr19-49168250-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0181 (2761/152292) while in subpopulation SAS AF = 0.0363 (175/4824). AF 95% confidence interval is 0.0319. There are 25 homozygotes in GnomAd4. There are 1327 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2761 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.449-10G>A		intron	N/A	NP_060106.2
	TRPM4	NM_001321281.2		c.268-303G>A		intron	N/A	NP_001308210.1
	TRPM4	NM_001195227.2		c.449-10G>A		intron	N/A	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.449-10G>A		intron	N/A	ENSP00000252826.4	Q8TD43-1
	TRPM4	ENST00000427978.6	TSL:1	c.449-10G>A		intron	N/A	ENSP00000407492.1	Q8TD43-3
	TRPM4	ENST00000595519.5	TSL:1	n.93-10G>A		intron	N/A	ENSP00000469893.1	M0QYK7

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2758 AN: 152174 Hom.: 25 Cov.: 30

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0358

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0201 AC: 5059 AN: 251324 AF XY: 0.0210

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00905

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0246

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0253 AC: 36922 AN: 1461724 Hom.: 549 Cov.: 34 AF XY: 0.0254 AC XY: 18439 AN XY: 727160

African (AFR) AF: 0.00379 AC: 127 AN: 33480

American (AMR) AF: 0.00919 AC: 411 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 352 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0336 AC: 2894 AN: 86246

European-Finnish (FIN) AF: 0.0288 AC: 1534 AN: 53316

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.0273 AC: 30318 AN: 1111962

Other (OTH) AF: 0.0208 AC: 1259 AN: 60394

GnomAD4 genome AF: 0.0181 AC: 2761 AN: 152292 Hom.: 25 Cov.: 30 AF XY: 0.0178 AC XY: 1327 AN XY: 74460

African (AFR) AF: 0.00513 AC: 213 AN: 41556

American (AMR) AF: 0.0118 AC: 180 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4824

European-Finnish (FIN) AF: 0.0279 AC: 296 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0268 AC: 1822 AN: 68030

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0233 Hom.: 75

Bravo AF: 0.0155

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	2	Progressive familial heart block type IB (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.7
DANN	Benign	0.74
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs78444754; hg19: chr19-49671507;