chr19-44708106-A-G

Position:

• chr19-44708106-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP5_Moderate BP4

The NM_001039213.4(CEACAM16):​c.1186A>G​(p.Thr396Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,458,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CEACAM16 NM_001039213.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.23

Genes affected

CEACAM16 (HGNC:31948): (CEA cell adhesion molecule 16, tectorial membrane component) The protein encoded by this gene is a secreted glycoprotein that in mouse interacts with tectorial membrane proteins in the inner ear. The encoded adhesion protein is found in cochlear outer hair cells and appears to be important for proper hearing over an extended frequency range. Defects in this gene likely are a cause of non-syndromic autosomal dominant hearing loss. [provided by RefSeq, May 2012]

CEACAM16-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 19-44708106-A-G is Pathogenic according to our data. Variant chr19-44708106-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38634208). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEACAM16	NM_001039213.4	c.1186A>G	p.Thr396Ala	missense_variant	6/7	ENST00000587331.7	NP_001034302.2
CEACAM16	XM_017026795.2	c.1186A>G	p.Thr396Ala	missense_variant	5/5		XP_016882284.1
CEACAM16-AS1	NR_186815.1	n.348-8929T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEACAM16	ENST00000587331.7	c.1186A>G	p.Thr396Ala	missense_variant	6/7	1	NM_001039213.4	ENSP00000466561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000166 AC: 4 AN: 241050 Hom.: 0 AF XY: 0.0000153 AC XY: 2 AN XY: 131122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000276

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1458470 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 725168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 06, 2016

The p.Thr396Ala variant in CEACAM16 has been reported by our laboratory in one i ndividual with hearing loss and segregated in three affected family members (thi s individual's family). This variant has been identified in 1/52160 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs755154488). Please note that for diseases with clinical variabili ty, reduced penetrance, or recessive inheritance, pathogenic variants may be pre sent at a low frequency in the general population. Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, although additional studies are required to full y establish its clinical significance, this variant is likely pathogenic for aut osomal dominant hearing loss based on the segregation of the variant in several individuals with hearing loss. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	.;N
REVEL	Benign	0.12
Sift	Benign	0.26	.;T
Sift4G	Uncertain	0.030	D;D
Vest4		0.48
MVP		0.81
MPC		0.54
ClinPred		0.68	D
GERP RS		5.9
Varity_R		0.099
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs755154488; hg19: chr19-45211378;