17-62395190-T-C

Variant names:

• chr17-62395190-T-C
• rs73329490
• NM_173503.4:c.488+2T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_173503.4(EFCAB3):​c.488+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000934 in 1,611,574 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: EFCAB3 NM_173503.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9816
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.57

Genes affected

EFCAB3 (HGNC:26379): (EF-hand calcium binding domain 3) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-62395190-T-C is Benign according to our data. Variant chr17-62395190-T-C is described in ClinVar as [Benign]. Clinvar id is 789844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0053 (806/152202) while in subpopulation AFR AF = 0.0184 (763/41516). AF 95% confidence interval is 0.0173. There are 4 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB3	NM_173503.4	c.488+2T>C		splice_donor_variant, intron_variant	Intron 6 of 9	ENST00000305286.8	NP_775774.1
EFCAB3	NM_001144933.2	c.644+2T>C		splice_donor_variant, intron_variant	Intron 8 of 11		NP_001138405.1
EFCAB3	XM_011524381.3	c.554+2T>C		splice_donor_variant, intron_variant	Intron 6 of 9		XP_011522683.2
EFCAB3	XM_011524380.2	c.488+2T>C		splice_donor_variant, intron_variant	Intron 6 of 9		XP_011522682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFCAB3	ENST00000305286.8	c.488+2T>C		splice_donor_variant, intron_variant	Intron 6 of 9	1	NM_173503.4	ENSP00000302649.3

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 804 AN: 152084 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00123 AC: 305 AN: 248832 AF XY: 0.000876

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.000650

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000479 AC: 699 AN: 1459372 Hom.: 6 Cov.: 31 AF XY: 0.000413 AC XY: 300 AN XY: 726030

Gnomad4 AFR exome AF: 0.0177 AC: 588 AN: 33282

Gnomad4 AMR exome AF: 0.000658 AC: 29 AN: 44052

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26012

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39680

Gnomad4 SAS exome AF: 0.0000584 AC: 5 AN: 85660

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53304

Gnomad4 NFE exome AF: 0.00000810 AC: 9 AN: 1111362

Gnomad4 Remaining exome AF: 0.00108 AC: 65 AN: 60274

GnomAD4 genome AF: 0.00530 AC: 806 AN: 152202 Hom.: 4 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74420

Gnomad4 AFR AF: 0.0184 AC: 0.0183785 AN: 0.0183785

Gnomad4 AMR AF: 0.00203 AC: 0.00202986 AN: 0.00202986

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207555 AN: 0.000207555

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588045 AN: 0.0000588045

Gnomad4 OTH AF: 0.00331 AC: 0.00331126 AN: 0.00331126

Alfa AF: 0.00208 Hom.: 6

Bravo AF: 0.00554

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Benign	0.97
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.85	D
GERP RS		6.0
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs73329490; hg19: chr17-60472551;