2-75051261-G-A

Variant names:

• chr2-75051261-G-A
• NM_001058.4:c.922C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001058.4(TACR1):​c.922C>T​(p.Leu308Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TACR1 NM_001058.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85
• Publications: 0 publications found

Genes affected

TACR1 (HGNC:11526): (tachykinin receptor 1) This gene belongs to a gene family of tachykinin receptors. These tachykinin receptors are characterized by interactions with G proteins and contain seven hydrophobic transmembrane regions. This gene encodes the receptor for the tachykinin substance P, also referred to as neurokinin 1. The encoded protein is also involved in the mediation of phosphatidylinositol metabolism of substance P. [provided by RefSeq, Sep 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TACR1	NM_001058.4	c.922C>T	p.Leu308Phe	missense_variant	Exon 4 of 5	ENST00000305249.10	NP_001049.1
TACR1	NM_015727.3	c.922C>T	p.Leu308Phe	missense_variant	Exon 4 of 4		NP_056542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TACR1	ENST00000305249.10	c.922C>T	p.Leu308Phe	missense_variant	Exon 4 of 5	1	NM_001058.4	ENSP00000303522.4
TACR1	ENST00000409848.3	c.922C>T	p.Leu308Phe	missense_variant	Exon 4 of 4	1		ENSP00000386448.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.922C>T (p.L308F) alteration is located in exon 4 (coding exon 4) of the TACR1 gene. This alteration results from a C to T substitution at nucleotide position 922, causing the leucine (L) at amino acid position 308 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.7	M;M
PhyloP100		6.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.62		Loss of catalytic residue at L308 (P = 0.0018);Loss of catalytic residue at L308 (P = 0.0018);
MVP		0.53
MPC		0.57
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.58
gMVP		0.73
Mutation Taster		=32/68	disease causing

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

hg19: chr2-75278388;