9-34709419-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_002989.4(CCL21):c.380G>A(p.Arg127Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,610,192 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: CCL21 NM_002989.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.626

Genes affected

CCL21 (HGNC:10620): (C-C motif chemokine ligand 21) 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. Similar to other chemokines the protein encoded by this gene inhibits hemopoiesis and stimulates chemotaxis. This protein is chemotactic in vitro for thymocytes and activated T cells, but not for B cells, macrophages, or neutrophils. The cytokine encoded by this gene may also play a role in mediating homing of lymphocytes to secondary lymphoid organs. It is a high affinity functional ligand for chemokine receptor 7 that is expressed on T and B lymphocytes and a known receptor for another member of the cytokine family (small inducible cytokine A19). [provided by RefSeq, Sep 2014]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066252947).
• BP6: Variant 9-34709419-C-T is Benign according to our data. Variant chr9-34709419-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2398484.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCL21	NM_002989.4	c.380G>A	p.Arg127Gln	missense_variant	4/4	ENST00000259607.7
PHF24	XM_047423102.1	c.133+6381C>T		intron_variant
PHF24	XM_047423103.1	c.70+6381C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCL21	ENST00000259607.7	c.380G>A	p.Arg127Gln	missense_variant	4/4	1	NM_002989.4	P1
	ENST00000664167.1	n.86+6381C>T		intron_variant, non_coding_transcript_variant
CCL21	ENST00000378792.1	c.*77G>A		3_prime_UTR_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000405 AC: 100 AN: 247110 Hom.: 0 AF XY: 0.000374 AC XY: 50 AN XY: 133824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000221

Gnomad SAS exome AF: 0.000264

Gnomad FIN exome AF: 0.000974

Gnomad NFE exome AF: 0.000534

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000255 AC: 372 AN: 1457920 Hom.: 2 Cov.: 31 AF XY: 0.000244 AC XY: 177 AN XY: 725464

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.000333

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000651 AC: 79

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	7.4
Dann	Benign	0.38
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.019
Sift	Benign	0.78	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.065
MVP		0.16
MPC		0.13
ClinPred		0.011	T
GERP RS		-1.4
Varity_R		0.029
gMVP		0.082

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148496138; hg19: chr9-34709416; COSMIC: COSV52398646;