9-34689965-G-A

Position:

• chr9-34689965-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006274.3(CCL19):​c.241C>T​(p.Arg81Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CCL19 NM_006274.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21

Genes affected

CCL19 (HGNC:10617): (C-C motif chemokine ligand 19) This antimicrobial gene is one of several CC cytokine genes clustered on the p-arm of chromosome 9. Cytokines are a family of secreted proteins involved in immunoregulatory and inflammatory processes. The CC cytokines are proteins characterized by two adjacent cysteines. The cytokine encoded by this gene may play a role in normal lymphocyte recirculation and homing. It also plays an important role in trafficking of T cells in thymus, and in T cell and B cell migration to secondary lymphoid organs. It specifically binds to chemokine receptor CCR7. [provided by RefSeq, Sep 2014]

PHF24 (HGNC:29180): (PHD finger protein 24) Predicted to enable metal ion binding activity. Predicted to act upstream of or within several processes, including detection of mechanical stimulus involved in sensory perception of pain; gamma-aminobutyric acid signaling pathway; and regulation of GABAergic synaptic transmission. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCL19	NM_006274.3	c.241C>T	p.Arg81Cys	missense_variant	3/4	ENST00000311925.7	NP_006265.1
PHF24	XM_047423102.1	c.48+8748G>A		intron_variant			XP_047279058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCL19	ENST00000311925.7	c.241C>T	p.Arg81Cys	missense_variant	3/4	1	NM_006274.3	ENSP00000308815.2
CCL19	ENST00000378800.3	c.241C>T	p.Arg81Cys	missense_variant	3/3	2		ENSP00000368077.3
CCL19	ENST00000485502.1	n.88C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The c.241C>T (p.R81C) alteration is located in exon 3 (coding exon 3) of the CCL19 gene. This alteration results from a C to T substitution at nucleotide position 241, causing the arginine (R) at amino acid position 81 to be replaced by a cysteine (C). 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	0.78
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-1.2	T
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.58
MutPred		0.48		Loss of MoRF binding (P = 0.0087);Loss of MoRF binding (P = 0.0087);
MVP		0.83
MPC		1.5
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.33
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs541327893; hg19: chr9-34689962; COSMIC: COSV61337401;