chr3-134603672-T-C

Variant names:

• chr3-134603672-T-C
• rs61745335
• NM_178554.6:c.1893A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_178554.6(KY):​c.1893A>G​(p.Thr631Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,613,802 control chromosomes in the GnomAD database, including 849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (421 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (428 hom.)
• Consequence: KY NM_178554.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.07
• Publications: 2 publications found

Genes affected

KY (HGNC:26576): (kyphoscoliosis peptidase) The protein encoded by this gene belongs to the transglutaminase-like superfamily. The protein is involved in the function, maturation and stabilization of the neuromuscular junction and may be required for normal muscle growth. Mutations in this gene are associated with myopathy, myofibrillar, 7. [provided by RefSeq, Apr 2017]

ENSG00000288700 (HGNC:):

CEP63 (HGNC:25815): (centrosomal protein 63) This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

CEP63 Gene-Disease associations (from GenCC):

• Seckel syndrome 6

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-134603672-T-C is Benign according to our data. Variant chr3-134603672-T-C is described in ClinVar as Benign. ClinVar VariationId is 1244064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178554.6. 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
	KY	NM_178554.6	MANE Select	c.1893A>G	p.Thr631Thr	synonymous	Exon 11 of 11	NP_848649.3
	KY	NM_001350859.2		c.1845A>G	p.Thr615Thr	synonymous	Exon 10 of 10	NP_001337788.1
	KY	NM_001366276.1		c.1830A>G	p.Thr610Thr	synonymous	Exon 10 of 10	NP_001353205.1	Q8NBH2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KY	ENST00000423778.7	TSL:5 MANE Select	c.1893A>G	p.Thr631Thr	synonymous	Exon 11 of 11	ENSP00000397598.2	Q8NBH2-4
	KY	ENST00000503669.1	TSL:1	c.*775A>G		3_prime_UTR	Exon 10 of 10	ENSP00000426777.1	B4DGA7
	KY	ENST00000864999.1		c.1839A>G	p.Thr613Thr	synonymous	Exon 11 of 11	ENSP00000535058.1

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5994 AN: 152214 Hom.: 420 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0104 AC: 2578 AN: 249028 AF XY: 0.00771

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000443

Gnomad OTH exome AF: 0.00662

GnomAD4 exome AF: 0.00436 AC: 6365 AN: 1461470 Hom.: 428 Cov.: 30 AF XY: 0.00374 AC XY: 2717 AN XY: 726988

African (AFR) AF: 0.148 AC: 4958 AN: 33476

American (AMR) AF: 0.00888 AC: 397 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.000348 AC: 387 AN: 1111756

Other (OTH) AF: 0.00898 AC: 542 AN: 60366

GnomAD4 genome AF: 0.0394 AC: 6002 AN: 152332 Hom.: 421 Cov.: 33 AF XY: 0.0385 AC XY: 2869 AN XY: 74490

African (AFR) AF: 0.137 AC: 5678 AN: 41560

American (AMR) AF: 0.0135 AC: 206 AN: 15306

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000676 AC: 46 AN: 68038

Other (OTH) AF: 0.0293 AC: 62 AN: 2116

Alfa AF: 0.0170 Hom.: 107

Bravo AF: 0.0447

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.14
DANN	Benign	0.54
PhyloP100		-4.1
Mutation Taster		=85/15	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: rs61745335; hg19: chr3-134322514;