rs199845217

Variant names:

• chr14-102497727-C-A
• rs199845217
• NM_014844.5:c.4081+8C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-102497727-C-A
• chr14-102497727-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_014844.5(TECPR2):​c.4081+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,597,186 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: TECPR2 NM_014844.5 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.440
• Publications: 0 publications found

Genes affected

TECPR2 (HGNC:19957): (tectonin beta-propeller repeat containing 2) The protein encoded by this gene is a member of the tectonin beta-propeller repeat-containing (TECPR) family, and contains both TECPR and tryptophan-aspartic acid repeat (WD repeat) domains. This gene has been implicated in autophagy, as reduced expression levels of this gene have been associated with impaired autophagy. Recessive mutations in this gene have been associated with a hereditary form of spastic paraparesis (HSP). HSP is characterized by progressive spasticity and paralysis of the legs. There is also some evidence linking mutations in this gene with birdshot chorioretinopathy (BSCR), which results in inflammation of the choroid and retina. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

TECPR2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 49

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 14-102497727-C-A is Benign according to our data. Variant chr14-102497727-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 540304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014844.5. 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
	TECPR2	NM_014844.5	MANE Select	c.4081+8C>A		splice_region intron	N/A	NP_055659.2	O15040-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECPR2	ENST00000359520.12	TSL:1 MANE Select	c.4081+8C>A		splice_region intron	N/A	ENSP00000352510.7	O15040-1
	TECPR2	ENST00000856897.1		c.4081+8C>A		splice_region intron	N/A	ENSP00000526956.1
	TECPR2	ENST00000971423.1		c.3748+8C>A		splice_region intron	N/A	ENSP00000641482.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000969 AC: 218 AN: 225004 AF XY: 0.00101

Gnomad AFR exome AF: 0.000394

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000362

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.000911

GnomAD4 exome AF: 0.00148 AC: 2139 AN: 1444858 Hom.: 4 Cov.: 32 AF XY: 0.00151 AC XY: 1083 AN XY: 716410

African (AFR) AF: 0.000301 AC: 10 AN: 33220

American (AMR) AF: 0.000526 AC: 23 AN: 43696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.00 AC: 0 AN: 39256

South Asian (SAS) AF: 0.000650 AC: 55 AN: 84594

European-Finnish (FIN) AF: 0.000529 AC: 27 AN: 51044

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.00178 AC: 1961 AN: 1102168

Other (OTH) AF: 0.00104 AC: 62 AN: 59584

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74490

African (AFR) AF: 0.000168 AC: 7 AN: 41580

American (AMR) AF: 0.000980 AC: 15 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00158 Hom.: 0

Bravo AF: 0.000986

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary spastic paraplegia 49 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	TECPR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: -4

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

Other links and lift over

dbSNP: rs199845217; hg19: chr14-102964064;