rs2662238

Variant names:

• chr5-83203488-G-A
• rs2662238
• NM_003401.5:c.483-64G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-83203488-G-A
• chr5-83203488-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003401.5(XRCC4):​c.483-64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,313,676 control chromosomes in the GnomAD database, including 131,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13518 hom., cov: 32)
  • Exomes 𝑓: 0.44 (117628 hom.)
• Consequence: XRCC4 NM_003401.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.172
• Publications: 11 publications found

Genes affected

XRCC4 (HGNC:12831): (X-ray repair cross complementing 4) The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]

XRCC4 Gene-Disease associations (from GenCC):

• short stature, microcephaly, and endocrine dysfunction

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• microcephalic primordial dwarfism-insulin resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-83203488-G-A is Benign according to our data. Variant chr5-83203488-G-A is described in ClinVar as Benign. ClinVar VariationId is 1230719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003401.5. 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
	XRCC4	NM_003401.5	MANE Select	c.483-64G>A		intron	N/A	NP_003392.1	Q13426-2
	XRCC4	NM_001318012.3		c.483-64G>A		intron	N/A	NP_001304941.1	Q13426-1
	XRCC4	NM_022406.5		c.483-64G>A		intron	N/A	NP_071801.1	Q13426-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC4	ENST00000396027.9	TSL:5 MANE Select	c.483-64G>A		intron	N/A	ENSP00000379344.4	Q13426-2
	XRCC4	ENST00000511817.1	TSL:1	c.483-64G>A		intron	N/A	ENSP00000421491.1	Q13426-1
	XRCC4	ENST00000282268.7	TSL:1	c.483-64G>A		intron	N/A	ENSP00000282268.3	Q13426-2

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62744 AN: 151708 Hom.: 13505 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.564

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.444 AC: 515979 AN: 1161850 Hom.: 117628 AF XY: 0.448 AC XY: 257446 AN XY: 574800

African (AFR) AF: 0.339 AC: 8026 AN: 23682

American (AMR) AF: 0.257 AC: 5109 AN: 19918

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 6806 AN: 18860

East Asian (EAS) AF: 0.218 AC: 7038 AN: 32278

South Asian (SAS) AF: 0.518 AC: 27816 AN: 53668

European-Finnish (FIN) AF: 0.516 AC: 23829 AN: 46210

Middle Eastern (MID) AF: 0.426 AC: 1603 AN: 3766

European-Non Finnish (NFE) AF: 0.454 AC: 414912 AN: 914790

Other (OTH) AF: 0.428 AC: 20840 AN: 48678

GnomAD4 genome AF: 0.413 AC: 62772 AN: 151826 Hom.: 13518 Cov.: 32 AF XY: 0.415 AC XY: 30802 AN XY: 74204

African (AFR) AF: 0.354 AC: 14674 AN: 41414

American (AMR) AF: 0.317 AC: 4835 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1256 AN: 3464

East Asian (EAS) AF: 0.204 AC: 1054 AN: 5172

South Asian (SAS) AF: 0.522 AC: 2512 AN: 4812

European-Finnish (FIN) AF: 0.521 AC: 5496 AN: 10540

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31470 AN: 67868

Other (OTH) AF: 0.407 AC: 857 AN: 2106

Alfa AF: 0.423 Hom.: 1761

Bravo AF: 0.389

Asia WGS AF: 0.358 AC: 1237 AN: 3462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.31
PhyloP100		0.17
Mutation Taster		=100/0	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: rs2662238; hg19: chr5-82499307; COSMIC: COSV56534362; COSMIC: COSV56534362;